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June 25, 2020

https://www.sciencedaily.com/releases/2020/06/200625102517.htm

From Jekyll to Hyde: New study pinpoints mutation that makes E. coli deadlier

As far as humans are concerned, bacteria can be classified as either harmful, pathogenic bacteria and harmless or beneficial non-pathogenic bacteria. To develop better treatments for diseases caused by pathogenic bacteria, we need to have a good grasp on the mechanisms that cause some bacteria to be virulent. Scientists have identified genes that cause virulence, or capability to cause disease, but they do not fully know how bacteria evolve to become pathogenic.

To find out, Professor Chikara Kaito and his team of scientists from Okayama University, Japan, used a process called experimental evolution to identify molecular mechanisms that cells develop to gain useful traits, and published their findings in The scientists decided to start with a non-pathogenic Through this experiment, the scientists created The mutations that increased bacterial deadliness appeared to give Researchers also identified the characteristics of substances that pathogenic strains were resistant to, showing that they were "hydrophobic" (or water-repelling) and positively charged. This fit with the increased amount of outer membrane vesicles, which are hydrophobic and negatively charged, allowing them to hold onto those substances (because, of course, opposite forces attract). The scientists also showed that the mutations occurred in parts of LPS transporter that are directly on the outside of the bacterial membrane. The scientists suspect that this is because these areas are more exposed to the environment, thereby experience more natural selection, and are thereby more susceptible to mutation."What we've done here is identify several things about pathogenic bacteria," explains Prof Kaito. "We showed for the first time that mutations to LPS transporter can increase virulence, and we provided evidence for how that virulence actually happens -- the mutant bacteria make more outer membrane vesicles." And that's not all, the team also pinpointed specific structural changes to mutated LPS transporter that could explain why virulence is different across bacteria -- because each species might have a different structure.When asked about how his work contributes to scientific understanding and to medicine, Prof Kaito elaborates, "Before our study, it wasn't very clear how bacteria actually evolved properties that made them more harmful, so our study helps clarify this. An understanding of this process means the possibility of creating drugs or other therapy that can keep bacteria from becoming pathogenic, especially if we find more proteins like LPS transporter, where mutations can have such a big effect."Of course, further studies are needed to explore whether the mutations observed in this study will also increase virulence when the bacteria infect animals bigger than silkworms, like mammals. But this study is definitely the first step toward unraveling the mystery of differences between dangerous and harmless bacteria.

Microbes

June 24, 2020

https://www.sciencedaily.com/releases/2020/06/200624172049.htm

Puget Sound eelgrass beds create a 'halo' with fewer harmful algae, new method shows

Eelgrass, a species of seagrass named for its long slippery texture, is one of nature's superheroes. It offers shade and camouflage for young fish, helps anchor shorelines, and provides food and habitat for many marine species.

A University of Washington study adds one more superpower to the list of eelgrass abilities: warding off the toxin-producing algae that regularly close beaches to shellfish harvests. Researchers found evidence that there are significantly fewer of the single-celled algae that produce harmful toxins in an area more than 45 feet, or 15 meters, around an eelgrass bed."We're not in the laboratory. The effect we're seeing is happening in nature, and it's an effect that's really widespread within this group of harmful algae. What we see is this halo of reduced abundance around the eelgrass beds," said Emily Jacobs-Palmer, a research scientist at the UW. She is the lead author of the study published this spring in the open-access journal Researchers sampled five coastal sites three times in the spring and summer of 2017. Four sites were within Puget Sound and one was in Willapa Bay, on Washington's outer coast.In addition to a traditional visual ecological survey at each site, the researchers used a type of genetic forensics to detect species that might not be easily seen or present at the time of the survey.Scientists put on waders and walked parallel to shore in water less than knee deep while scooping up seawater samples to analyze the environmental DNA, or eDNA, present. This method collects fragments of genetic material to identify organisms living in the seawater.The researchers sampled water from each site at the same point in the tidal cycle both inside the eelgrass bed and at regular intervals up to 45 feet away from the edge. For comparison they also surveyed a location farther away over bare seabed."In the DNA fragments we saw everything from shellfish to marine worms, osprey, bugs that fell in the water," Jacobs-Palmer said. "It's quite fascinating to just get this potpourri of organisms and then look for patterns, rather than deciding on a pattern that we think should be there and then looking for that."The researchers analyzed the eDNA results to find trends among 13 major groups of organisms. They discovered that dinoflagellates, a broad class of single-celled organism, were scarcer in and around the eelgrass beds than in surrounding waters with bare seabed."We were asking how the biological community changes inside eelgrass beds, and this result was so strong that it jumped out at us, even though we weren't looking for it specifically," said senior author Ryan Kelly, a UW associate professor of marine and environmental affairs.The result has practical applications, since certain species of dinoflagellate populations can spike and produce toxins that accumulate in shellfish, making the shellfish dangerous or even deadly to eat.The phrase "harmful algal bloom" has a formal definition that was not measured for this study. But authors say the trend appeared when the overall dinoflagellate populations were high."I have heard people talk about a trade-off between shellfish and eelgrass, in terms of land use in Puget Sound. Now, from our perspective, there's not a clean trade-off between those things -- these systems might be able to complement one another," Kelly said.To explore the reasons for the result, the authors looked at differences in water chemistry or current motion around the bed. But neither could explain why dinoflagellate populations were lower around the eelgrass.Instead, the authors hypothesize that the same biological reasons why dinoflagellates don't flourish inside eelgrass beds -- likely bacteria that occur with eelgrass and are harmful to dinoflagellates -- may extend past the bed's edge."It was known that there is some antagonistic relationship between eelgrass and algae, but it's really important that this effect seems to span beyond the bounds of the bed itself," Jacobs-Palmer said.The discovery of a "halo effect" by which eelgrass discourages the growth of potentially harmful algae could have applications in shellfish harvesting, ecological restoration or shoreline planning."These beds are often really large, and that means that their perimeter is also really large," Jacobs-Palmer said. "That's a lot of land where eelgrass is potentially having an effect."In follow-up work, researchers chose two of the sites, in Port Gamble on the Kitsap Peninsula and Skokomish on Hood Canal, to conduct weekly sampling from late June through October 2019. They hope to verify the pattern they discovered and learn more about the environmental conditions that might allow the halo to exist.

Microbes

June 24, 2020

https://www.sciencedaily.com/releases/2020/06/200624151539.htm

Entry point for curbing the evolution of antibiotic resistance discovered

The team of Professor Tobias Bollenbach from the Institute for Biological Physics at the University of Cologne has published a study on a new approach to improving the effectiveness of antibiotics in bacterial infections. The study 'Highly parallel lab evolution reveals that epistasis can curb the evolution of antibiotic resistance,' on ways to controlling antibiotic resistance through targeted gene interactions has appeared in '

'We wanted to know how genetic disorders in the bacterium E. coli interact with the later evolutionary adaptation to the drug,' said Bollenbach. Doctoral researcher Marta Luka?išinová developed a robotic platform together with Bollenbach and the technician Booshini Fernando with which hundreds of genetically altered Escherichia coli populations could be created simultaneously, and the course of their evolution investigated. 'Our most important result was that we found an entry point for suppressing the spontaneous development of resistance to the administered drug,' Luka?išinová added.At first, the team identified a prototypical pattern in the development of resistance: Those bacterial strains that initially reacted more sensitively to drugs developed a greater resistance to the drug during the course of the evolutionary experiment. However, the researchers were particularly interested in the conditions under which this pattern is broken and virtually no resistance develops. The study showed that this happens when the bacterium exhibits certain functional disorders. The researchers identified the areas of membrane transport and chaperones, which play a decisive role in the error-free production of proteins. If these functions are not fully intact in the bacterium, an antibiotic can attack these areas much more effectively and improve its effectiveness in the long term. In the future, these molecular targets may help to improve antibiotics.As head of the 'Biological Physics and Systems Biology' research group at the University of Cologne, Tobias Bollenbach is investigating new ways to minimize or even prevent the development of drug resistance.

Microbes

June 24, 2020

https://www.sciencedaily.com/releases/2020/06/200624103234.htm

Bacterial predator could help reduce COVID-19 deaths

A type of virus that preys on bacteria could be harnessed to combat bacterial infections in patients whose immune systems have been weakened by the SARS-CoV-2 virus that causes the COVID-19 disease, according to an expert at the University of Birmingham and the Cancer Registry of Norway.

Called bacteriophages, these viruses are harmless to humans and can be used to target and eliminate specific bacteria. They are of interest to scientists as a potential alternative to antibiotic treatments.In a new systematic review, published in the journal In the first approach, bacteriophages would be used to target secondary bacterial infections in patients' respiratory systems. These secondary infections are a possible cause of the high mortality rate, particularly among elderly patients. The aim is to use the bacteriophages to reduce the number of bacteria and limit their spread, giving the patients' immune systems more time to produce antibodies against SARS-CoV-2.Dr Marcin Wojewodzic, a Marie Skłodowska-Curie Research Fellow in the School of Biosciences at the University of Birmingham and now researcher at the Cancer Registry of Norway, is the author of the study. He says: "By introducing bacteriophages, it may be possible to buy precious time for the patients' immune systems and it also offers a different, or complementary strategy to the standard antibiotic therapies."Professor Martha R.J. Clokie, a Professor of Microbiology at the University of Leicester and Editor-in-Chief of PHAGE journal explains why this work is important: "In the same way that we are used to the concept of 'friendly bacteria' we can harness 'friendly viruses' or 'phages' to help us target and kill secondary bacterial infections caused by a weakened immune system following viral attack from viruses such as COVID-19."Dr Antal Martinecz, an expert in computational pharmacology at the Arctic University of Norway who advised on the manuscript says: "This is not only a different strategy to the standard antibiotic therapies but, more importantly, it is exciting news relating to the problem of bacterial resistance itself."In the second treatment strategy, the researcher suggests that synthetically altered bacteriophages could be used to manufacture antibodies against the SARS-CoV-2 virus which could then be administered to patients via a nasal or oral spray. These bacteriophage-generated antibodies could be produced rapidly and inexpensively using existing technology."If this strategy works, it will hopefully buy time to enable a patient to produce their own specific antibodies against the SARS-CoV-2 virus and thus reduce the damage caused by an excessive immunological reaction," says Dr Wojewodzic.Professor Martha R.J. Clokie's research focuses on the identification and development of bacteriophages that kill pathogens in an effort to develop new antimicrobials: "We could also exploit our knowledge of phages to engineer them to generate novel and inexpensive antibodies to target COVID-19. This clearly written article covers both aspects of phage biology and outlines how we might use these friendly viruses for good purpose."Dr Wojewodzic is calling for clinical trials to test these two approaches."This pandemic has shown us the power viruses have to cause harm. However, by using beneficial viruses as an indirect weapon against the SARS-CoV-2 virus and other pathogens, we can harness that power for a positive purpose and use it to save lives. The beauty of nature is that while it can kill us, it can also come to our rescue." adds Dr Wojewodzic."It's clear that no single intervention will eliminate COVID-19. In order to make progress we need to approach the problem from as many different angles and disciplines as possible." concludes Dr Wojewodzic.

Microbes

June 23, 2020

https://www.sciencedaily.com/releases/2020/06/200623145358.htm

Slow-growing rotavirus mutant reveals early steps of viral assembly

Rotavirus is responsible for more than 130,000 deaths in infants and young children younger than five years, every year. The virus causes severe, dehydrating diarrhea as it replicates in viral factories called viroplasms that form inside infected cells. Viroplasms have been difficult to study because they normally form very quickly, but a serendipitous observation led researchers at Baylor College of Medicine to uncover new insights into the formation of viroplasms.

The researchers created a mutant rotavirus that unexpectedly replicated much slower than the original virus, allowing them to observe the first steps of viral assembly. The findings, published in the "The formation of viroplasms is indispensable for a successful rotavirus infection. They form quickly inside infected cells and are made of both viral and cellular proteins that interact with lipid droplets, but the details of how the parts are put together are still not clear," said first author Dr. Jeanette M. Criglar, a former postdoctoral trainee and now staff scientist in the Department of Molecular Virology and Microbiology at Baylor in Dr. Mary Estes's lab.To get new insights into the formation of viroplasms, Criglar and her colleagues studied NSP2, one of the viral proteins that is required for the virus to replicate. Without it, neither viroplasms nor new viruses would form.Like all proteins, NSP2 is made of amino acids strung together like beads on a necklace. 'Bead' 313 is the amino acid serine. Importantly, serine 313 is phosphorylated -- it has a phosphate chemical group attached to it. Protein phosphorylation is a mechanism cells use to regulate protein activity. It works like an on-and-off switch, activating or deactivating a protein. Here, the researchers evaluated the role NSP2's phosphorylation of serine 313 plays on viroplasm formation.Using a recently developed reverse genetics system, Criglar and her colleagues generated a rotavirus carrying an NSP2 protein with a mutation in amino acid 313, called a phosphomimetic mutation, by changing serine to aspartic acid. The name phosphomimetic indicates that the mutant protein mimics the phosphorylated protein in the original rotavirus. Reverse genetics starts with a protein and works backward to make the mutant gene, which then is made part of the virus to study the function of the protein on viral behavior."In laboratory experiments, our phosphomimetic mutant protein crystalized faster than the original, within hours as opposed to days," Criglar said. "But surprisingly, when compared to non-mutant rotavirus, the phosphomimetic virus was slow to make viroplasms and to replicate.""This is not what we expected. We thought that rotavirus with the mutant protein also would replicate faster," said Estes, Cullen Foundation Endowed Chair and Distinguished Service Professor of molecular virology and microbiology at Baylor. "We took advantage of the delay in viroplasm formation to observe very early events that have been difficult to study."The researchers discovered that one of the first steps in viroplasm formation is the association of NSP2 with lipid droplets, indicating that NSP2 phosphorylated on position 313 alone can interact with the droplets, without interacting with other components of the viroplasm.Lipid droplets are an essential part of viroplasms. It is known that rotavirus coaxes infected cells to produce the droplets, but how it does it is unknown. The new findings suggest that rotavirus may be using phosphorylated NSP2 to trigger lipid droplet formation."It was very exciting to see that just changing a single amino acid in the NSP2 protein affected the replication of the whole virus," Criglar said. "The phosphomimetic change altered the dynamics of viral replication without killing the virus. We can use this mutant rotavirus to continue investigating the sequence of events leading to viroplasm formation, including a long-standing question in cell biology about how lipid droplets form.""This is the first study in our lab that has used the reverse genetics system developed for rotavirus by Kanai and colleagues in Japan, and that's very exciting for me," Estes said. "There have been very few papers that use the system to ask a biological question, and ours is one of them."

Microbes

June 23, 2020

https://www.sciencedaily.com/releases/2020/06/200623145350.htm

Universal flu vaccine may be more challenging than expected

Some common strains of influenza have the potential to mutate to evade broad-acting antibodies that could be elicited by a universal flu vaccine, according to a study led by scientists at Scripps Research.

The findings highlight the challenges involved in designing such a vaccine, and should be useful in guiding its development.In the study, published in One of the main goals of current influenza research is to develop a universal vaccine that induces broadly neutralizing antibodies, also known as "bnAbs," to give people long-term protection from the flu."These results show that in designing a universal flu vaccine or a universal flu treatment using bnAbs, we need to figure out how to make it more difficult for the virus to escape via resistance mutations," says the study's senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at Scripps Research.Influenza causes millions of cases of illness around the world every year and at least several hundred thousand fatalities. Flu viruses have long posed a challenge for vaccine designers because they can mutate rapidly and vary considerably from strain to strain.The mix of strains circulating in the population tends to change every flu season, and existing flu vaccines can induce immunity against only a narrow range of recently circulating strains. Thus, current vaccines provide only partial and temporary, season-by-season protection.Nevertheless, scientists have been working toward developing a universal flu vaccine that could provide long-term protection by inducing an immune response that includes bnAbs. Over the past decade, several research groups, including Wilson's, have discovered these multi-strain neutralizing antibodies in recovering flu patients, and have analyzed their properties. But to what extent circulating flu viruses can simply mutate to escape these bnAbs has not been fully explored.In the study, first-authored by postdoctoral research associate Nicholas Wu, PhD, and staff scientist Andrew Thompson, PhD, the team examined whether an H3N2 flu virus could escape neutralization by two of the more promising flu bnAbs that have been discovered so far.Known as CR9114 and FI6v3, these antibodies bind to a critical region on the virus structure called the hemagglutinin stem, which doesn't vary much from strain to strain. Because of their broad activity against different flu strains, they've been envisioned as antibodies that a universal flu vaccine should be designed to elicit, and also as ingredients in a future therapy to treat serious flu infections.Using genetic mutations to methodically alter one amino acid building-block of the protein after another at the stem site where the bnAbs bind, Wu and colleagues found many single and double mutations that can allow H3N2 flu to escape the antibodies' infection-blocking effect.The team also found a few instances of these "resistance mutations" in a database of gene sequences from circulating flu strains, suggesting that the mutations already happen occasionally in a small subset of ordinary flu viruses.Although experiments and analyses suggested that H3N2 viruses are broadly capable of developing resistance mutations, the same was not true for H1N1 viruses. The researchers tested several H1N1 viruses and found that none seemed able to mutate and escape, except for rare mutations with weak escape effects. The H3N2 and H1N1 subtypes account for most of the flu strains circulating in humans.The researchers used structural biology techniques to show how differences in the hemagglutinin stem structure allow H3N2 flu viruses to develop resistance mutations to the two stem-binding antibodies more easily than H1N1 viruses."If it's relatively easy for H3N2 to escape those bnAbs, which are the prototype antibodies that a universal flu vaccine should induce, then we probably need to think more carefully and rigorously about the design of that universal flu vaccine against certain influenza subtypes," Wu says. "The good news is that a universal flu vaccine should at least work well against the H1N1 subtype."The researchers now plan to conduct similar studies with other flu subtypes and bnAbs. They say that in principle, a vaccine eliciting multiple bnAbs that attack different sites on flu viruses or are more accommodating to changes in the virus could help mitigate the problem of resistance mutations.

Microbes

June 23, 2020

https://www.sciencedaily.com/releases/2020/06/200623145346.htm

Prenatal stress associated with infant gut microbes

Mother's chronic prenatal psychological distress and elevated hair cortisol concentrations are associated with gut microbiota composition of the infant, according to a new publication from the FinnBrain research project of the University of Turku, Finland. The results help to better understand how prenatal stress can be connected to infant growth and development. The study has been published in the

Prenatal stress can be associated with infant growth and development. However, the mechanisms underlying this association are not yet fully understood."We were able to show that maternal chronic psychological distress and elevated hair cortisol concentrations during pregnancy are associated with infant gut microbiota composition but not diversity," says Doctoral Candidate, Doctor Anna Aatsinki.The study used hair cortisol analysis which enabled measuring the concentration averages of stress hormone cortisol over several months. In addition, the symptoms of the mother were assessed three times during pregnancy. The infant gut microbiota was analysed early at the age of 2.5 months with next generation sequencing.Previously, similar studies have focused on animals and two have been smaller human studies making this data consisting of 399 mothers and their infants the largest in the world so far. The received results provide significant new information on the phenomenon. In addition, this study was able to confirm previously made observations.Both Proteobacteria and Lactobacillus are common infant gut microbes."We discovered, for instance, that mother's chronic prenatal psychological distress was linked to increased abundances of Proteobacteria genera in infant microbiota. In addition, chronic psychological symptoms were connected to decreased abundances of Akkermansia genera which is considered to promote health at least in adults," summarises Aatsinki.According to Aatsinki, it was also interesting that low cortisol concentrations were associated with increased abundances of Lactobacillus in infant gut microbiota. Lactobacillus bacteria are considered to promote health.However, Proteobacteria also contain species that are able to cause inflammation in the body. Proteobacteria can also be associated with the child's disease risk later in life. Therefore, researchers consider it important to study how the observed changes are connected to later child development."Our study does not explain the cause-effect relationship, or whether prenatal psychological stress is linked to differences in microbial metabolic products or e.g. in immune system function. In other words, important questions still need to be answered," notes Aatsinki.The study is part of the FinnBrain research project and its gut-brain axis sub-project. The sub-project led by Docent, Child and Adolescent Psychiatrist Linnea Karlsson studies how prenatal stress affects infant microbiota development and how infant gut microbes affect later brain development.The FinnBrain research project of the University of Turku studies the combined influence of environmental and genetic factors on the development of children. Over 4,000 families participate in the research project and they are followed from infancy long into adulthood.

Microbes

June 23, 2020

https://www.sciencedaily.com/releases/2020/06/200623104236.htm

Current serotype of dengue virus in Singapore disguises itself to evade vaccines and therapeutics

Dengue infections are rising, even as public health authorities are battling to contain the spread of the coronavirus. Dengue virus serotype 2 (DENV2) had previously been the predominant serotype but DENV3 has re-emerged in Singapore after almost three decades. This means the Singapore population has lower immunity to DENV3 and, consequently, a large proportion of the population is susceptible to DENV3 infection.

So far, there are no highly protective vaccines or therapeutic agents that target DENV. This is due to the possibility that antibodies raised against any one of the four known serotypes (DENV1-4) may enhance disease severity when an individual is infected with a different serotype in a secondary infection. This suggests an effective vaccine has to be able to stimulate equally strong protective responses simultaneously against all four serotypes. Adding further complication to vaccine development is the fact that there are different virus strains within each serotype, and different strains can exhibit vastly different shapes, enabling them to escape detection by a host's immune system. The Duke-NUS team had previously discovered that the surface of the DENV2 can change from smooth to bumpy depending on host conditions."Previous structural work focused mostly on DENV2, and therefore the other serotypes that are equally important are not well studied," said Professor Sheemei Lok from the Duke-NUS' Emerging Infectious Diseases (EID) programme and corresponding author of this study. "In this study, we found that DENV3 can dramatically transform itself from a smooth, round particle to a club-shaped particle -- like golf clubs, which would help the virus to evade hosts' immune response, vaccines and therapeutics."The team also found some strains capable of transforming into club-shaped particles in DENV1, DENV2 and zika, though these exist as a minority of the virus population. Nonetheless, this suggests that flaviviruses have the potential to turn themselves into a conformation that is vastly different from their original structure, which can make vaccines and therapeutics ineffective against them."While Singapore has seen a recent spike in dengue cases, annually this virus infects about 400 million people worldwide, with a high prevalence in tropical and sub-tropical regions. In line with Duke-NUS vision of transforming medicine, this study gives new direction to developing better therapies and vaccines to treat or prevent dengue infections, and contribute to public health outcomes," said Prof Patrick Casey, Senior Vice Dean for Research at Duke-NUS.The team is currently studying more DENV3 clinical strains to determine if this structural transformation is common.

Microbes

June 23, 2020

https://www.sciencedaily.com/releases/2020/06/200623100126.htm

Tongue microbes provide window to heart health

Microorganisms on the tongue could help diagnose heart failure, according to research presented today on HFA Discoveries, a scientific platform of the European Society of Cardiology (ESC).1

"The tongues of patients with chronic heart failure look totally different to those of healthy people," said study author Dr. Tianhui Yuan, No.1 Hospital of Guangzhou University of Chinese Medicine. "Normal tongues are pale red with a pale white coating. Heart failure patients have a redder tongue with a yellow coating and the appearance changes as the disease becomes more advanced.""Our study found that the composition, quantity and dominant bacteria of the tongue coating differ between heart failure patients and healthy people," she said.Previous research has shown that microorganisms in the tongue coating could distinguish patients with pancreatic cancer from healthy people.2 The authors of that study proposed this as an early marker to diagnose pancreatic cancer. And, since certain bacteria are linked with immunity, they suggested that the microbial imbalance could stimulate inflammation and disease. Inflammation and the immune response also play a role in heart failure.3This study investigated the composition of the tongue microbiome in participants with and without chronic heart failure. The study enrolled 42 patients in hospital with chronic heart failure and 28 healthy controls. None of the participants had oral, tongue or dental diseases, had suffered an upper respiratory tract infection in the past week, had used antibiotics and immunosuppressants in the past week, or were pregnant or lactating.Stainless steel spoons were used to take samples of the tongue coating in the morning, before participants had brushed their teeth or eaten breakfast. A technique called 16S rRNA gene sequencing was used to identify bacteria in the samples.The researchers found that heart failure patients shared the same types of microorganisms in their tongue coating. Healthy people also shared the same microbes. There was no overlap in bacterial content between the two groups.At the genus level, five categories of bacteria distinguished heart failure patients from healthy people with an area under the curve (AUC) of 0.84 (where 1.0 is a 100% accurate prediction and 0.5 is a random finding).In addition, there was a downward trend in levels of Eubacterium and Solobacterium with increasingly advanced heart failure.Dr. Yuan said: "More research is needed, but our results suggest that tongue microbes, which are easy to obtain, could assist with wide-scale screening, diagnosis, and long-term monitoring of heart failure. The underlying mechanisms connecting microorganisms in the tongue coating with heart function deserve further study."

Microbes

June 22, 2020

https://www.sciencedaily.com/releases/2020/06/200622182127.htm

Myxobacteria's ability to distinguish self from non-self

A fundamental question in biology is how individual cells within a multicellular organism interact to coordinate diverse processes.

A University of Wyoming researcher and his Ph.D. students studied myxobacteria -- common soil microbes that prey off other microbes for food -- and posed the question: "How do cells from a diverse environment recognize other cells as related or clonal to build social groups and a multicellular organism?""Myxobacteria assemble a multicellular organism by cobbling together cells from their environment. This is in contrast to plants and animals, where gametes fuse to create a unique cell, which, upon clonal expansion, creates a multicellular organism," says Dan Wall, a professor in the UW Department of Molecular Biology. "The ability of myxobacteria to create multicellular organisms is remarkable, given that soil is considered to be the most diverse environment on the planet, wherein a small sample can consist of tens of thousands of microbial species. Broadly speaking, our work helps to address this question."Wall is corresponding author of a paper, titled "Rapid Diversification of Wild Social Groups Driven by Toxin-Immunity Loci on Mobile Genetic Elements," that was published in the June 22 (today) issue of the IChristopher Vassallo and Vera Troselj, both Ph.D. candidates in Wall's lab at the time of the research, are co-authors of the paper. Vassallo and Troselj are now postdoctoral researchers at the Massachusetts Institute of Technology and the Lawrence Berkeley National Laboratory, respectively. Michael Weltzer, a UW graduate student in the Molecular and Cellular Life Sciences program from Idaho Springs, Colo., is another co-author.This work is mostly fundamental and addresses how cells discriminate between the self and non-self, Wall says."Multicellularity is a difficult way of life to evolve and maintain, because cells are the smallest unit of life, and there is selective pressure for them to exploit their environment, including other cells, for their own benefit," he explains. "For example, cancer cells do this and are constantly arising in our own body. Fortunately, our immune system recognizes them as non-self and eliminates them. Our system works in an analogous manner."Wall says his group's work builds on prior research on the subject that showed that a small patch of soil has another layer of remarkable diversity at the subspecies level. Among Myxococcus xanthus isolates, there are many different social groups that discriminate against one another. However, Wall says the prior research did not elucidate how it works at the molecular level."Our paper addresses the mechanism of how they (myxobacteria) discriminate and how highly related strains recently diverged, or evolved, into distinct social groups," Wall says.This ISME paper also builds on Vassallo and Wall's previous paper, titled "Self-Identify Barcodes Encoded in Expansive Polymorphic Toxin Families Discriminate Kin in Myxobacteria," that was published in the The work in the Thus, if the other cells are true clonemates, they have genetically encoded immunity to those toxins. But if they are divergent cells that happen to have compatible TraA receptors, but are not clonemates, they will be killed by toxin transfer. In the From the "We analyzed the publicly available genomes of those 22 (myxobacteria) strains, identified their toxin genes and predicted how they would socially interact," Wall says. "We found a perfect correlation between our predictions and empirical findings by others. We then experimentally tested our predictions by creating mutants and showed we could engineer social harmony between otherwise antagonistic strains by inactivating toxin transfer."Along with the TraA delivery/discrimination system, Wall says they also discovered two other systems -- type VI secretion system (T6SS) and rearrangement hotspot (RHS) -- were involved in kin discrimination. T6SS is a molecular injection apparatus that transfers toxins into adjacent cells. If the cells are clonal, they will encode immunity; if not, they will be intoxicated. T6SSs are widely distributed in many different types of bacteria. Although not well understood, the RHS system also serves as a nanoweapon.Additionally, the group showed that the key discriminatory toxin genes resided on mobile genetic elements in the chromosome. That is, these highly related strains recently diverged by the horizontal transfer of genes in their environment, mediated by virus-like particles.

Microbes

June 22, 2020

https://www.sciencedaily.com/releases/2020/06/200622172026.htm

Hamsters develop protective immunity to COVID-19 and are protected by convalescent sera

In an animal model for COVID-19 that shares important features of human disease, scientists at the University of Wisconsin-Madison, the University of Tokyo and the Icahn School of Medicine at Mount Sinai show that prior infection with the SARS-CoV-2 virus provides protection against reinfection, and treatment with convalescent serum limits virus replication in their lungs.

Syrian hamsters, commonly found as pets, have served critical roles in understanding human infectious diseases for decades. The new study, led by Yoshihiro Kawaoka and published today (June 22, 2020) in the "Hamsters are good models for human influenza and SARS-CoV," says Kawaoka, professor of pathobiological sciences at the UW School of Veterinary Medicine and a virology professor at the University of Tokyo. "This is why we decided to study them with COVID-19. We wanted to see if the disease course is similar to humans in these animals from beginning to end."A study led by scientists at the University of Hong Kong, published in late March, also showed Syrian hamsters to be a good model for COVID-19-related research. In that study, the hamsters lost weight, became lethargic, and developed other outward signs of illness.Kawaoka's group extended this work further, demonstrating that both low and high doses of the virus, from patient samples collected in the U.S. and Japan, replicate well in the airways of juvenile hamsters (1 month old) and adults (7 to 8 months old). The virus can also infect both the upper and lower respiratory tracts.The research team also showed that SARS-CoV-2 causes severe disease in the lungs of infected animals. This includes lesions and the kind of "ground glass" appearance often found in lung scans in human patients. Scans also revealed a region of gas in the cavity surrounding the hamster's lungs, indicating severe lung damage. Researchers observed the most severe effects within eight days after infection, and improvement by 10 days."Hamsters infected with SARS-CoV-2 share CT imaging characteristics with human COVID-19 disease," says Samantha Loeber, a veterinarian and radiologist at UW Veterinary Care.By day 10 following infection, the researchers no longer detected virus in the organs of most of the hamsters, but lung damage persisted for 14 days in a majority of the animals, and for at least 20 days in most of those infected with a high dose.Overall, the researchers were able to detect virus in all of the respiratory organs of the infected hamsters within six days of infection, and also from samples collected from their brains, though these also contained portions of the olfactory bulb, which is involved in smell and may have been the source of virus in these samples. The initial dose of the virus did not affect how much of the virus researchers ultimately found in the hamster's organs.The researchers also looked for but did not detect virus in the kidneys, the small intestine, the colon or in blood.To determine whether hamsters developed antibodies against SARS-CoV-2 that protected them from reinfection, the researchers administered another round of the virus to a number of the same animals about three weeks following initial infection and were unable to detect virus in their respiratory tracts. They did find virus in the airways of control animals not previously infected."The animals all possessed antibodies and did not get sick again, which suggests they developed protective immunity," says Pete Halfmann, a research professor in Kawaoka's U.S. lab. "But we still can't say how long this protection lasts."In early April, researchers across the U.S., including at the UW School of Medicine and Public Health and UW Health, initiated a clinical trial to examine whether the antibody-bearing component of blood -- the plasma or sera -- from recovered COVID-19 patients could be given to sick patients to assist in their recovery. While convalescent plasma has been used in other disease outbreaks, it remains poorly understood as a treatment.So, Kawaoka's team extracted convalescent sera from previously sick hamsters and then pooled it together. They infected new hamsters with SARS-CoV-2 and then gave them this antibody-laden sera either one day or two days following infection.The hamsters that received treatment within a day of infection had much lower amounts of infectious virus in their nasal passages and lungs than those given a mock treatment. Those that received sera on day two showed a less appreciable benefit, though they still had lower levels of virus in their respiratory organs compared to control animals.A study published just last week in "This shows us that convalescent sera, still experimental in human patients, may be part of an effective treatment for COVID-19," Kawaoka adds.Finally, the research team also obtained the first images of the internal features of the SARS-CoV-2 virus that aid its ability to replicate, or make copies of itself, in host cells. This, Kawaoka says, warrants further study.The study was supported by the Japan Research Program on Emerging and Re-emerging Infectious Diseases, the Japan Project Promoting Support for Drug Discovery, the Japan Initiative for Global Research Network on Infectious Diseases, the Japan Agency for Medical Research and Development Program for Infectious Diseases Research and Infrastructure, and the U.S. National Institutes of Allergy and Infectious Diseases.

Microbes

June 22, 2020

https://www.sciencedaily.com/releases/2020/06/200622133041.htm

Bread mold avoids infection by mutating its own DNA

Whilst most organisms try to stop their DNA from mutating, scientists from the UK and China have discovered that a common fungus found on bread actively mutates its own DNA as a way of fighting virus-like infections.

All organisms mutate all of the time. You were born with between ten and a hundred new mutations, for example. Many do little harm but, if they hit one of your genes, mutations are much more likely to be harmful than beneficial. If harmful enough they contribute to genetic diseases.Whilst mutations can enable species to adapt, most mutations are harmful, and so evolutionary biologists have postulated that natural selection will always act to reduce the mutation rate.While prior data has supported this view, recent work by Professor Laurence Hurst of the Milner Centre for Evolution at the University of Bath (UK) and Sihai Yang, Long Wang and colleagues at Nanjing University (China) have found that Neurospora crassa, a type of bread mould, is a remarkable exception to the rule.Professor Hurst, Director of the Milner Centre for Evolution at the University of Bath, said: "Many organisms have a problem with transposable elements, otherwise called jumping genes."These are virus-like bits of DNA that insert themselves into their host's DNA, copy themselves and keep on inserting -- hence the name jumping genes."Organisms have found different ways of combatting this nuisance, many of which try to prevent the transposable elements from expressing their own genes. Neurospora has evolved a different solution: it hits them exceptionally hard with mutations to rapidly degrade them."The study, published in To understand how RIP affects the fungus's own DNA, the team sequenced the whole genome from both parents and offspring for many strains of Neurospora to see how many mutations could be found and where they were in the DNA.Overall, they found that each base pair in the Neurospora genome has about a one in a million chance of mutating every generation; over a hundred times higher than any non-viral life on the planet.Professor Hurst said: "This was a real surprise to us -- any organism that hits its own genes with that many mutations is likely one that will not persist for very long. It would be like opening up the back of a watch, stabbing at all the cog wheels that look a bit similar and expecting the watch to still function!"Our findings show that Neurospora has not only a high mutation rate but is also a massive outlier. It appears to use RIP to destroy transposable elements but at a cost, with considerable collateral damage."This organism thus goes against the standard theory for mutation rate evolution which proposes that selection should always act to reduce the mutational burden."It is the exception that proves the rule."

Microbes

June 22, 2020

https://www.sciencedaily.com/releases/2020/06/200622133018.htm

Pioneering research reveals certain human genes relate to gut bacteria

The role genetics and gut bacteria play in human health has long been a fruitful source of scientific inquiry, but new research marks a significant step forward in unraveling this complex relationship. Its findings could transform our understanding and treatment of all manner of common diseases, including obesity, irritable bowel syndrome, and Alzheimer's disease.

The international study, led by the University of Bristol and published today in Lead author Dr David Hughes, Senior Research Associate in Applied Genetic Epidemiology, said: "Our findings represent a significant breakthrough in understanding how genetic variation affects gut bacteria. Moreover, it marks major progress in our ability to know whether changes in our gut bacteria actually cause, or are a consequence of, human disease."The human body comprises various unique ecosystems, each of which is populated by a vast and diverse array of microorganisms. They include millions of bacteria in the gut, known as the microbiome, that help digest food and produce molecules essential for life, which we cannot produce ourselves. This has prompted researchers to question if gut bacteria may also directly influence human health and disease.Previous research has identified numerous genetic changes apparently related to bacterial composition in the gut, but only one such association has been observed consistently. This example involves a well-known single mutation that changes whether someone can digest the sugar (lactose) in fresh milk. The same genetic variation also predicts the prevalence of bacteria, Bifidobacterium, that uses or digests lactose as an energy source.This study, the biggest of its kind, identified 13 DNA changes related to changes in the presence or quantity of gut bacteria. Researchers at Bristol worked with Katholieke Universiteit Leuven and Christian-Albrecht University of Kiel to analyse data from 3,890 individuals from three different population studies: one in Belgium (the Flemish Gut Flora Project) and two in Germany (Food Chain Plus and PopGen). In each individual, the researchers measured millions of known DNA changes and, by sampling their feces, also registered the presence and abundance of hundreds of gut bacteria.Dr Hughes said: "It was exciting to identify new and robust signals across the three study populations, which makes the correlation of genetic variation and gut bacteria much more striking and compelling. Now comes the great challenge of confirming our observations with other studies and dissecting how exactly these DNA changes might impact bacterial composition."Such investigations could hold the key to unlocking the intricate biological mechanisms behind some of the biggest health challenges of our time.Study co-author Dr Kaitlin Wade, Lecturer in Epidemiology at the University of Bristol, said: "A strength here is that these findings provide a groundwork for causal analyses to determine, for instance, whether the presence of specific bacteria increases the risk of a disease or is a manifestation of it.""The implications for our understanding of human health and our approach to medicine are far-reaching and potentially game changing."

Microbes

June 22, 2020

https://www.sciencedaily.com/releases/2020/06/200622132948.htm

Washing away stubborn biofilms using fungal cleaning products

Lurking inside pipes and on the surfaces of indwelling medical devices, slimy layers of bacteria, called biofilms, cause problems ranging from largescale product contamination to potentially fatal chronic infections. Biofilms are notoriously difficult to eliminate -- not surprising given that one of their main functions is to protect encased bacteria from threats such as predation, antibiotics, and chemical cleaning agents.

Bleach, harsh oxidizing cleaning products, and petrochemical-derived detergents called surfactants combined with scrubbing are the most effective methods of removing biofilms. However, bleach and harsh chemicals are obviously unsuitable for use in biological settings, and while surfactants are used in products such as hand soap and cosmetics, many are toxic to the environment and can damage the surfaces that they are used on.But in a study published this month in peer-reviewed journal "Certain Candida yeasts can naturally produce biosurfactants called sophorolipids during the fermentation of oils," explains co-lead author Professor Andrew Utada. "Previous studies have shown that sophorolipids have some degree of antimicrobial activity, but there is conflicting information on the effects of these compounds on biofilms composed of the Gram-negative pathogen Pseudomonas aeruginosa."Gram-negative bacteria such as P. aeruginosa and Escherichia coli are a major cause of hospital-acquired infections, killing thousands of people every year. Using microfluidic channels, the researchers showed that sophorolipids do a better job of disrupting established P. aeruginosa biofilms than commonly used chemical surfactants.Surprisingly though, there was no evidence that sophorolipids actually killed the bacteria. A mutant P. aeruginosa strain that produces excessive amounts of biofilm matrix was therefore used to examine the underlying mechanism of biofilm dispersal, revealing that sophorolipids appear to weaken the interaction between the biofilm and the underlying surface and break the internal cohesiveness of the biofilm itself, leading to disruption.Although biosurfactants are biodegradable and far less harmful to the environment than their chemical counterparts, they are costly to produce. To address this issue, the researchers tested the effects of sophorolipids in combination with the widely used chemical surfactant sodium dodecyl sulfate, with encouraging results."Combination testing revealed a synergy between sophorolipids and chemical surfactants, with the two agents together demonstrating stronger antibiofilm effects at concentrations about 100-fold lower than when either one was used in isolation," says Ph.D. candidate Bac Nguyen.Although reducing the costs associated with the production of biosurfactants is the long-term goal, this synergistic approach to biofilm elimination may open new doors for the treatment of persistent bacterial biofilm-mediated infections.

Microbes

June 19, 2020

https://www.sciencedaily.com/releases/2020/06/200619104310.htm

Fungal pathogen disables plant defense mechanism

Cabbage plants defend themselves against herbivores and pathogens by deploying a defensive mechanism called the mustard oil bomb: when the plant tissue is damaged, toxic isothiocyanates are formed and can effectively fend off attackers. Researchers at the Max Planck Institute for Chemical Ecology and the University of Pretoria have now been able to show in a new study that this defense is also effective to some extent against the widespread and detrimental fungus Sclerotinia sclerotiorum. However, the pathogen uses at least two different detoxification mechanisms that enable the fungus to successfully spread on plants defended in this way. The metabolic products thus formed are non-toxic to the fungus, allowing it to grow on these plants.

Sclerotinia sclerotiorum is a devastating fungal pathogen that can infect more than 400 different plant species. The main symptom of the disease called Sclerotinia wilt or white mold is wilting. Visible are also the white, cotton-like fungal spores that overgrow plant leaves and stalks. In agriculture, rapeseed cultivation is particularly at risk. The plant disease can affect other members of the cabbage family, and also potatoes, legumes and strawberries.Scientists at the Max Planck Institute for Chemical Ecology in Jena have long been studying the glucosinolates and isothiocyanates that constitute the special defense mechanism of cabbage family plants, which include rapeseed, radishes and mustard. "We wanted to find out how successful plant pathogens overcome the plant defense and colonize these plants. We therefore asked ourselves whether widespread fungal pathogens have strategies to adapt to the chemical defenses of plants of the cabbage family," Jingyuan Chen, the first author of the study, explains.The researchers were able to show experimentally that the defense based on glucosinolates is actually effective against fungal attacks. However, they also discovered two different strategies of the white mold fungus to detoxify the defensive substances: The first is a general detoxification pathway that binds glutathione to the isothiocyanate toxins. This type of detoxification of organic poisons is quite common in insects and even mammals. The second and far more effective way to render the isothiocyanates harmless is to hydrolyse them, i.e. to cleave them enzymatically with a water molecule. The researchers wanted to identify the enzymes and corresponding genes underlying this detoxification mechanism. Genes that enable the successful detoxification of these substances had already been described in bacteria. They are called Sax genes after experiments with the model plant Arabidopsis thaliana: Survival in Arabidopsis eXtracts."We based our search on the known bacterial SaxA proteins to select candidate genes for further investigations. We then tested whether these genes are actually expressed in greater quantities in fungi exposed to the toxins, and whether the resulting protein can render the toxins harmless," explains Daniel Vassão, one of the study leaders. Using high-resolution analytical methods, the scientists were able to identify and quantify the metabolites produced by the fungus during detoxification. They also used mutants of the fungus in which the SaxA-encoding gene had been knocked out for comparison. This revealed that the Sax protein of the white mold fungus is active against a range of isothiocyanates, allowing it to colonize different plants of the cabbage family.Mutants lacking the gene for this detoxification pathway were dramatically reduced in their capacity to tolerate isothiocyanates. "However, it was surprising to see that these mutants up-regulated their general pathway of detoxification, although this did not compensate for the mutation," says Jingyuan Chen. Glutathione conjugation cannot detoxify isothiocyanates nearly as effectively as hydrolysis can. Although it seems to be metabolically more expensive for the fungus, this general pathway is always present as it helps the fungus to detoxify a huge variety of poisons. "It is possible that this general pathway protects the fungus initially, while the machinery required for the more specialized pathway is assembled after an initial exposure to the toxin and can take over later in the infection," says Daniel Vassão.In further experiments, the researchers want to investigate whether other fungi that successfully infect plants of the cabbage family also detoxify isothiocyanates via the same pathway, and whether unrelated fungal species are also able to degrade these toxins. "Then we will know whether this widespread detoxification is due to repeated evolution in fungi colonizing mustards, or is a feature which has been conserved over time and is therefore found in many fungal lines," Jonathan Gershenzon, director of the Department of Biochemistry where the research was conducted, concludes.

Microbes

June 18, 2020

https://www.sciencedaily.com/releases/2020/06/200618120213.htm

Viruses can steal our genetic code to create new human-virus genes

Like a scene out of "Invasion of the Body Snatchers," a virus infects a host and converts it into a factory for making more copies of itself. Now researchers have shown that a large group of viruses, including the influenza viruses and other serious pathogens, steal genetic signals from their hosts to expand their own genomes.

This finding is presented in a study published online today and in print June 25 in The cross-disciplinary team of virologists looked at a large group of viruses known as segmented negative-strand RNA viruses (sNSVs), which include widespread and serious pathogens of humans, domesticated animals and plants, including the influenza viruses and Lassa virus (the cause of Lassa fever). They showed that, by stealing genetic signals from their hosts, viruses can produce a wealth of previously undetected proteins. The researchers labeled them as UFO (Upstream Frankenstein Open reading frame) proteins, as they are encoded by stitching together the host and viral sequences. There was no knowledge of the existence of these kinds of proteins prior to this study.These UFO proteins can alter the course of viral infection and could be exploited for vaccine purposes."The capacity of a pathogen to overcome host barriers and establish infection is based on the expression of pathogen-derived proteins," said Ivan Marazzi, PhD, Associate Professor of Microbiology at Icahn School of Medicine and corresponding author on the study. "To understand how a pathogen antagonizes the host and establishes infection, we need to have a clear understanding of what proteins a pathogen encodes, how they function, and the manner in which they contribute to virulence."Viruses cannot build their own proteins, so they need to feed suitable instructions to the machinery that builds proteins in their host's cells. Viruses are known to do this through a process called "cap-snatching," in which they cut the end from one of the cell's own protein-encoding messages (a messenger RNA, or mRNA) and then extend that sequence with a copy of one of their own genes. This gives a hybrid message to be read."For decades we thought that by the time the body encounters the signal to start translating that message into protein (a 'start codon') it is reading a message provided to it solely by the virus. Our work shows that the host sequence is not silent," said Dr. Marazzi.The researchers show that, because they make hybrids of host mRNAs with their own genes, viruses (sNSVs) can produce messages with extra, host-derived start codons, a process they called "start snatching." This makes it possible to translate previously unsuspected proteins from the hybrid host-virus sequences. They further show that these novel genes are expressed by influenza viruses and potentially a vast number of other viruses. The product of these hybrid genes can be visible to the immune system, and they can modulate virulence. Further studies are needed to understand this new class of proteins and what the implications are of their pervasive expression by many of the RNA viruses that cause epidemics and pandemics.Ed Hutchinson, PhD, corresponding author and a research fellow at MRC-University of Glasgow Centre for Virus Research, said, "Viruses take over their host at the molecular level, and this work identifies a new way in which some viruses can wring every last bit of potential out of the molecular machinery they are exploiting. While the work done here focusses on influenza viruses, it implies that a huge number of viral species can make previously unsuspected genes."Researchers say the next part of their work is to understand the distinct roles the unsuspected genes play. "Now we know they exist, we can study them and use the knowledge to help disease eradication," said Dr. Marazzi. "A large global effort is required to stop viral epidemics and pandemics, and these new insights may lead to identifying novel ways to stop infection."This study was supported by funders including the National Institute of Allergy and Infectious Diseases and the UK Medical Research Council.

Microbes

June 17, 2020

https://www.sciencedaily.com/releases/2020/06/200617150006.htm

Earth's species have more in common than previously believed

The Earth hosts an abundance of life forms -- from well-known animals and plants to small, more hardy life forms such as archaea, viruses and bacteria. These life forms are fundamentally different all the way down to the cell level. Or so scientists thought.

Now an international team of researchers has analysed the proteins found in 100 different species -- from bacteria and archaea to plants and humans. It is the largest protein mapping ever to be conducted across different species.They have learned that these life forms in fact have a number of common characteristics. The study is a collaboration between researchers in Professor Matthias Mann's group in the Novo Nordisk Foundation Center for Protein Research and the Max Planck Institute of Biochemistry. It has been published in the top scientific journal 'We have mapped the proteins, together called the proteome of 100 different species. And it is obvious that they are extremely different. At the same time, though, they have more in common than we thought. In all these life forms, a large share of the proteins focus on metabolism and on maintaining a protein balance', says Professor Matthias Mann.Previously, researchers were mainly interested in the DNA of various organisms. For example, how much genetic material humans share with different animals. However, with advancements in the technology used for studying organisms at molecular level, researchers have turned to proteins the workhorses of the cell.'A common characteristic of all these life forms is the fact that a high percentage of their proteomes focus on maintaining a sort of balance, what is called as homeostasis. Another common characteristic is the fact that a large share of the proteins help to generate energy. Even though the ways in which this is done differ -- from photosynthesis to carbohydrate burning', says Alberto Santos Delgado who during the studies was employed at the Novo Nordisk Foundation Center for Protein Research.The researchers have used an advanced technology called mass spectrometry to study all 100 species. The technology enabled them to double the number of proteins confirmed experimentally.Previous research has predicted how many and which proteins exist based only on the genetic code and bioinformatic calculations. However, the new protein mapping has provided actual data on the existence of a very large number of new proteins.'Our work connecting quantitative mass spectrometry-based proteomics with database resources has resulted in a data set of eight million data points with 53 million interconnections. We made all the data publicly available, enabling other researchers to use it to identify new correlations. New technologies enabled by machine learning are on the rise and we expect those to benefit from the large and uniform dataset we provide publicly', says PhD Student Johannes Mueller from the Max Planck Institute of Biochemistry.The researchers at the University of Copenhagen focussed on data processing and bioinformatics analysis, while the researchers at the Max Planck Institute of Biochemistry in Munich focussed on mass spectrometry.On the website Proteomes of Life, the researchers made all data from the project publicly available.The study was funded by the Max Planck Society for the Advancement of Science, the EU Horizon 2020 programme and the Novo Nordisk Foundation.

Microbes

June 17, 2020

https://www.sciencedaily.com/releases/2020/06/200617145959.htm

RNA structures by the thousands

Researchers from Bochum and Münster have developed a new method to determine the structures of all RNA molecules in a bacterial cell at once. In the past, this had to be done individually for each molecule. Besides their exact composition, their structure is crucial for the function of the RNAs. The team describes the new high-throughput structure mapping method, termed Lead-Seq for lead sequencing, in the journal Nucleic Acids Research, published online on 28 May 2020.

Christian Twittenhoff, Vivian Brandenburg, Francesco Righetti and Professor Franz Narberhaus from the Chair of Microbial Biology at Ruhr-Universität Bochum (RUB) collaborated with the bioinformatics group headed by Professor Axel Mosig at RUB and the team led by Professor Petra Dersch at the University of Münster, previously from the Helmholtz Centre for Infection Research in Braunschweig.In all living cells, genetic information is stored in double-stranded DNA and transcribed into single-stranded RNA, which then serves as a blueprint for proteins. However, RNA is not only a linear copy of the genetic information, but often folds into complex structures. The combination of single-stranded and partially folded double-stranded regions is of central importance for the function and stability of RNAs. "If we want to learn something about RNAs, we must also understand their structure," says Franz Narberhaus.With lead sequencing, the authors present a method that facilitates the simultaneous analysis of all RNA structures in a bacterial cell. In the process, the researchers take advantage of the fact that lead ions cause strand breaks in single-stranded RNA segments; folded RNA structures, i.e. double strands, remain untouched by lead ions.By applying lead, the researchers split the single-stranded RNA regions at random locations into smaller fragments, then transcribed them into DNA and sequenced them. The beginning of each DNA sequence thus corresponded to a former strand break in the RNA. "This tells us that the corresponding RNA regions were present as a single strand," explains Narberhaus.Vivian Brandenburg and Axel Mosig then used bioinformatics to evaluate the information on the single-stranded RNA sections obtained in the experiments. "We assumed that non-cut RNA regions were present as double strands and used prediction programs to calculate how the RNA molecules must be folded," elaborates Vivian Brandenburg. "This resulted in more reliable structures with the information from lead sequencing than without this information."This approach enabled the researchers to simultaneously determine the structures of thousands of RNAs of the bacterium Yersinia pseudotuberculosis all at once. The team compared the results obtained by lead sequencing of some RNA structures with results obtained using traditional methods -- they were both the same.The group carried out their experiments at 25 and 37 degrees Celsius, since some RNA structures change depending on the temperature. Using what is known as RNA thermometers, bacteria such as the diarrhoea pathogen Yersinia pseudotuberculosis can detect whether they are inside the host. Using lead sequencing, the team not only identified already known RNA thermometers, but also discovered several new ones.Establishing lead sequencing took about five years. "I'm happy to say that we are now able to map numerous RNA molecules in a bacterium simultaneously," concludes Franz Narberhaus. "One advantage of the method is that the small lead ions can easily enter living bacterial cells. We therefore assume that this method can be used universally and will in future facilitate the detailed structure-function analysis of bacterial RNAs."

Microbes

June 17, 2020

https://www.sciencedaily.com/releases/2020/06/200617121511.htm

Microbes might manage your cholesterol

In the darkest parts of the world where light fails to block out the unfathomable bounty of the stars, look up. There are still fewer specks illuminating the universe than there are bacteria in the world, hidden from sight, a whole universe inside just one human gut.

Many species are known, like "The metabolism of cholesterol by these microbes may play an important role in reducing both intestinal and blood serum cholesterol concentrations, directly impacting human health," said Emily Balskus, professor of chemistry and chemical biology at Harvard University and co-senior author with Ramnik Xavier, , core member at the Broad, co-director of the Center for informatics and therapeutics at MIT and investigator at Massachusetts General Hospital. The newly discovered bacteria could one day help people manage their cholesterol levels through diet, probiotics, or novel treatments based on individual microbiomes.According to the Centers for Disease Control and Prevention (CDC), in 2016, over 12 percent of adults in the United States age 20 and older had high cholesterol levels, a risk factor for the country's number one cause of death: heart disease. Only half of that group take medications like statins to manage their cholesterol levels; while such drugs are a valuable tool, they don't work for all patients and, though rare, can have concerning side effects."We're not looking for the silver bullet to solve cardiovascular disease," Kenny said, "but there's this other organ, the microbiome, another system at play that could be regulating cholesterol levels that we haven't thought about yet."Since the late 1800s, scientists knew that something was happening to cholesterol in the gut. Over decades, work inched closer to an answer. One study even found evidence of cholesterol-consuming bacteria living in a hog sewage lagoon. But those microbes preferred to live in hogs, not humans.Prior studies are like a case file of clues (one 1977 lab even isolated the telltale microbe but the samples were lost). One huge clue is coprostanol, the byproduct of cholesterol metabolism in the gut. "Because the hog sewage lagoon microbe also formed coprostanol," said Balskus, "we decided to identify the genes responsible for this activity, hoping we might find similar genes in the human gut."Meanwhile, Damian Plichta, a computational scientist at the Broad Institute and co-first author with Kenny, searched for clues in human data sets. Hundreds of species of bacteria, viruses and fungi that live in the human gut have yet to be isolated and described, he said. But so-called metagenomics can help researchers bypass a step: Instead of locating a species of bacteria first and then figuring out what it can do, they can analyze the wealth of genetic material found in human microbiomes to determine what capabilities those genes encode.Plichta cross-referenced massive microbiome genome data with human stool samples to find which genes corresponded with high levels of coprostanol. "From this massive amount of correlations," he said, "we zoomed in on a few potentially interesting genes that we could then follow up on." Meanwhile, after Balskus and Kenny sequenced the entire genome of the cholesterol-consuming hog bacterium, they mined the data and discovered similar genes: A signal that they were getting closer.Then Kenny narrowed their search further. In the lab, he inserted each potential gene into bacteria and tested which made enzymes to break down cholesterol into coprostanol. Eventually, he found the best candidate, which the team named the Intestinal Steroid Metabolism A (IsmA) gene."We could now correlate the presence or absence of potential bacteria that have these enzymes with blood cholesterol levels collected from the same individuals," said Xavier. Using human microbiome data sets from China, Netherlands and the United States, they discovered that people who carry the IsmA gene in their microbiome had 55 to 75 percent less cholesterol in their stool than those without."Those who have this enzyme activity basically have lower cholesterol," Xavier said.The discovery, Xavier said, could lead to new therapeutics -- like a "biotic cocktail" or direct enzyme delivery to the gut -- to help people manage their blood cholesterol levels. But there's a lot of work to do first: The team may have identified the crucial enzyme, but they still need to isolate the microbe responsible. They need to prove not just correlation but causation -- that the microbe and its enzyme are directly responsible for lowering cholesterol in humans. And, they need to analyze what effect coprostanol, the reaction byproduct, has on human health."It doesn't mean that we're going to have answers tomorrow, but we have an outline of how to go about it," Xavier said.

Microbes

June 17, 2020

https://www.sciencedaily.com/releases/2020/06/200617121455.htm

Using tiny electrodes to measure electrical activity in bacteria

Scientists at Laboratory of Organic Electronics, Linköping University, have developed an organic electrochemical transistor that they can use to measure and study in fine detail a phenomenon known as extracellular electron transfer in which bacteria release electrons.

The study of bacteria and their significance for the natural world, and for human society and health, is a growing research field, as new bacteria are continuously being discovered. A human body contains more bacteria than human cells, and a millilitre of fresh water can hold as many as a million bacteria. Respiration in a normal human cell and in many bacteria takes place through biochemical reactions in which a compound, often glucose, reacts with oxygen to form carbon dioxide and water. During the process, energy is converted to a form that the cell can use. In oxygen-free environments, bacteria are found that metabolise organic compunds, like lactate, and instead of forming water, they release, or respire, electric charges, a by product of metabolism, into the environment. The process is known as extracellular electron transfer, or extracellular respiration.The phenomenon is currently used in several electrochemical systems in applications such as water purification, biosensors and fuel cells. Adding bacteria is an eco-friendly way to convert chemical energy to electricity.One such bacteria often used in research is Shewanella oneidensis, which previous research has shown to produce electrical current when fed with arsenic, arabinose (a type of sugar) or organic acids. A similar bacterium has recently been discovered in the human gastrointestinal system.We do not, however, understand in detail what happens when bacteria release charges. In order to capture and measure the amount of charge released, electrodes are placed into the microbial systems. An individual bacterium gives a very weak signal, and thus until now, researchers have had to be satisfied with studying extracellular electron transfer in large systems with large numbers of bacteria.In order to increase our understanding, scientists at the Laboratory of Organic Electronics at Linköping University have employed a combination of microelectronics, electrochemistry and microbiology. They have developed an organic electrochemical transistor in which they have been able to deposit Shewanella oneidensis on one of the microelectrodes, with a surface area of only a quarter of a square millimetre. The amplification of the signal that occurs in the transistor makes it possible for them to study in detail what happens when various substances are added to the system. They describe in an article in "We have shown that we can detect very small differences in extracellular electron transfer, in other words the amount of charge released by the bacteria. Another plus is that we can achieve very short response times, and obtain a stable signal within ten minutes," says principal research engineer Gábor Méhes, who, together with senior lecturer Eleni Stavrinidou, is corresponding author for the article."This is a first step towards understanding extracellular electron transfer in bacteria occupying olny a small area with the help of a transistor, and how the conversion takes place between the bacteria and the electrode," says Gábor Méhes. "One future goal is to learn how bacteria interact with each other, and with other cells and chemical substances in the human gastrointestinal tract."The research is being conducted within the framework of the Biocom Lab at the Laboratory of Organic Electronics, and is financed by Vinnova, the Swedish Research Council, the Swedish Foundation for Strategic Research, the Wallenberg Wood Science center and the European Research Council, ERC.It is hoped that the research will lead to optimising microbial electrochemical systems that harvest energy, and increase our understanding of, for example, serious gastrointestinal conditions. Looking far inte the future, the idea has been raised among reserachers of using bacteria that respire iron compounds to support human life on the oxygen-free planet Mars.

Microbes

June 16, 2020

https://www.sciencedaily.com/releases/2020/06/200616113927.htm

Could the cure for IBD be inside your mouth?

While many people put off their regular trips to the dentist, recent research has shown that the consequences of doing so may go beyond cavities and root canals. From heart disease to diabetes, poor oral health is often a reflection of a person's overall health and may even be the cause of systemic disease.

A new collaborative study from the U-M Medical and Dental Schools reveals that inflammatory bowel disease (IBD), which included Crohn's disease and ulcerative colitis and afflicts an estimated 3 million adults in the U.S., may be the latest condition made worse by poor oral health.Nobuhiko Kamada, Ph.D., assistant professor of internal medicine in the division of gastroenterology, has been studying the gut microbiome -- the collection of bacteria that are normally present in the gut -- for years. He noted an emerging link in research literature between an overgrowth of foreign bacterial species in the guts of people with IBD -- bacteria that are normally found in the mouth. "I decided to approach the dental school to ask the question, does oral disease affect the severity of gastrointestinal diseases?" says Kamada.The new mouse study, published in In the first pathway, periodontitis, the scientific name for gum disease, leads to an imbalance in the normal healthy microbiome found in the mouth, with an increase of bacteria that cause inflammation. These disease-causing bacteria then travel to the gut.However, this alone may not be enough to set off gut inflammation. The team demonstrated that oral bacteria may aggravate gut inflammation by looking at microbiome changes in mice with inflamed colons."The normal gut microbiome resists colonization by exogenous, or foreign, bacteria," says Kamada. "However, in mice with IBD, the healthy gut bacteria are disrupted, weakening their ability to resist disease-causing bacteria from the mouth." The team found that mice with both oral and gut inflammation had significantly increased weight loss and more disease activity.In the second proposed pathway, periodontitis activates the immune system's T cells in the mouth. These mouth T cells travel to the gut where they, too, exacerbate inflammation. The gut's normal microbiome is held in balance by the action of inflammatory and regulatory T cells that are fine-tuned to tolerate the resident bacteria. But, says Kamada, oral inflammation generates mostly inflammatory T cells that migrate to the gut, where they, removed from their normal environment, end up triggering the gut's immune response, worsening disease."This exacerbation of gut inflammation driven by oral organisms that migrate to the gut has important ramifications in emphasizing to patients the critical need to promote oral health as a part of total body health and wellbeing," says co-author William Giannobile, DDS, the William K and Mary Anne Najjar professor of dentistry and chair of the department of periodontics and oral medicine at the U-M School of Dentistry.The study has implications for novel treatments for IBD, necessary because "far too many patients still fail medications, leading to reduced quality of life and eventual surgery," says study co-author Shrinivas Bishu, M.D., assistant professor of gastroenterology. "This study importantly implies that clinical outcomes in IBD may be improved by monitoring oral inflammation -- an intriguing concept."

Microbes

June 15, 2020

https://www.sciencedaily.com/releases/2020/06/200615140840.htm

Super-potent human antibodies protect against COVID-19 in animal tests

A team led by Scripps Research has discovered antibodies in the blood of recovered COVID-19 patients that provide powerful protection against SARS-CoV-2, the coronavirus that causes the disease, when tested in animals and human cell cultures.

The research, published today in "The discovery of these very potent antibodies represents an extremely rapid response to a totally new pathogen," says study co-senior author Dennis Burton, PhD, the James and Jessie Minor Chair in Immunology in the Department of Immunology & Microbiology at Scripps Research.In principle, injections of such antibodies could be given to patients in the early stage of COVID-19 to reduce the level of virus and protect against severe disease. The antibodies also may be used to provide temporary, vaccine-like protection against SARS-CoV-2 infection for healthcare workers, elderly people and others who respond poorly to traditional vaccines or are suspected of a recent exposure to the coronavirus.The project was led by groups at Scripps Research; IAVI, a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges; and University of California San Diego School of Medicine."It has been a tremendous collaborative effort, and we're now focused on making large quantities of these promising antibodies for clinical trials," says co-lead author Thomas Rogers, MD, PhD, an adjunct assistant professor in the Department of Immunology & Microbiology at Scripps Research, and assistant professor of Medicine at UC San Diego.Developing a treatment or vaccine for severe COVID-19 is currently the world's top public health priority. Globally, almost 8 million people have tested positive for SARS-CoV-2 infection, and more than 400,000 have died of severe COVID-19. The daily toll of new infections is still rising.One approach to new viral threats is to identify, in the blood of recovering patients, antibodies that neutralize the virus's ability to infect cells.These antibodies can then be mass-produced, using biotech methods, as a treatment that blocks severe disease and as a vaccine-like preventive that circulates in the blood for several weeks to protect against infection. This approach already has been demonstrated successfully against Ebola virus and the pneumonia-causing respiratory syncytial virus, commonly known as RSV.For the new project, Rogers and his UC San Diego colleagues took blood samples from patients who had recovered from mild-to-severe COVID-19. In parallel, scientists at Scripps Research and IAVI developed test cells that express ACE2, the receptor that SARS-CoV-2 uses to get into human cells. In a set of initial experiments, the team tested whether antibody-containing blood from the patients could bind to the virus and strongly block it from infecting the test cells.The scientists were able to isolate more than 1,000 distinct antibody-producing immune cells, called B cells, each of which produced a distinct anti-SARS-CoV-2 antibody. The team obtained the antibody gene sequences from these B cells so that they could produce the antibodies in the laboratory. By screening these antibodies individually, the team identified several that, even in tiny quantities, could block the virus in test cells, and one that could also protect hamsters against heavy viral exposure.All of this work -- including the development of the cell and animal infection models, and studies to discover where the antibodies of interest bind the virus -- was completed in less than seven weeks."We leveraged our institution's decades of expertise in antibody isolation and quickly pivoted our focus to SARS-CoV-2 to identify these highly potent antibodies," says study co-author Elise Landais, PhD, an IAVI principal scientist.If further safety tests in animals and clinical trials in people go well, then conceivably the antibodies could be used in clinical settings as early as next January, the researchers say."We intend to make them available to those who need them most, including people in low- and middle-income countries," Landais says.In the course of their attempts to isolate anti-SARS-CoV-2 antibodies from the COVID-19 patients, the researchers found one that can also neutralize SARS-CoV, the related coronavirus that caused the 2002-2004 outbreak of severe acute respiratory syndrome (SARS) in Asia."That discovery gives us hope that we will eventually find broadly neutralizing antibodies that provide at least partial protection against all or most SARS coronaviruses, which should be useful if another one jumps to humans," Burton says."Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model" was co-authored by 30 scientists including lead authors Thomas Rogers, Fangzhu Zhao, Deli Huang, and Nathan Beutler, all of Scripps Research. The corresponding authors were Devin Sok and Joseph Jardine of IAVI, and Dennis Burton of Scripps Research.Funding was provided by the National Institutes of Health (UM1 AI44462), the IAVI Neutralizing Antibody Center, the Bill and Melinda Gates Foundation (OPP 1170236, OPP 1206647, OPP1196345/ INV-008813), the John and Mary Tu Foundation, and the Pendleton Foundation.

Microbes

June 15, 2020

https://www.sciencedaily.com/releases/2020/06/200615115824.htm

A continental-scale prediction on the functional diversity of stream microbes

A recent research find indicates that climate change increases the functional diversity of microbes living in streams. Consequently, climate change may, in certain cases, be beneficial to ecosystems.

The functional genes of microbes and their sufficient diversity are important indicators of the efficiency of ecosystem processes. Bacteria, single-celled fungi and other microbes are an essential element of the nutrient cycle, and their functional diversity boosts the decomposition of organic carbon.Stream microbe samples were collected in a collaboration among Finnish, Spanish and Chinese researchers. In previous studies utilising the material collected from mountainous areas in Norway, Spain and China, the focus has been on the species of stream microbes. Now, the frozen samples have been used to identify a total of nearly 16,000 functional genes of three different microbial groups, in addition to which the researchers have completed a forecast encompassing Europe and Asia.The article, published in the Based on observations made in the field, a forecast was completed on how the diversity and composition of functional genes will change across Eurasia as a result of climate change."We saw that the diversity of functional genes in microbes decreases in mountainous areas when moving from warm valleys towards the colder peaks," Professor Janne Soininen says.Therefore, the functional diversity of microbes is likely to grow as the climate becomes warmer, while ecosystem processes vital to waterways, such as the decomposition of organic matter and nutrient cycling, may become increasingly efficient.In the case of Eurasia, the change will be most marked in its northern regions where the diversity of functional genes can grow by as much as 30% and the composition of functional genes can change by as much as 35% by 2060-2080 compared to the current situation, depending on the climate scenario used.

Microbes

June 15, 2020

https://www.sciencedaily.com/releases/2020/06/200615115814.htm

Tuberculosis spread from animals to humans may be greater than previously thought

The number of human tuberculosis (TB) cases that are due to transmission from animals, as opposed to human-to-human transmission, may be much higher than previously estimated, according to an international team of researchers. The results could have implications for epidemiological studies and public health interventions.

"Tuberculosis kills 1.4 million people every year, making it the most deadly disease arising from a single infectious agent," said Vivek Kapur, professor of microbiology and infectious diseases and Huck Distinguished Chair in Global Health, Penn State. "India has the largest burden of human tuberculosis globally, with more than 2.6 million cases and 400,000 deaths reported in 2019. Additionally, the cattle population in India exceeds 300 million, and nearly 22 million of these were estimated to be infected with TB in 2017.Kapur noted that the World Health Organization, World Organisation for Animal Health and Food and Agriculture Organization of the United Nations define zoonotic TB as human infection with Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex (MTBC).To evaluate the use of M. bovis as a proxy for zoonotic tuberculosis and to investigate the potential role of other MTBC subspecies, Kapur and his colleagues analyzed 940 bacterial samples -- both pulmonary (from lung fluid or tissue) and extrapulmonary (from tissues other than the lungs) -- collected from patients who were visiting a large reference hospital for TB in southern India. The researchers used PCR to speciate M. tuberculosis complex organisms and then sequenced all the non-M. tuberculosis samples. Next, they compared the sequences to 715 sequences from cattle and humans that had previously been collected in south Asia and submitted to public databases."Surprisingly, we did not find any evidence for the presence of M. bovis in any of the samples," said Sreenidhi Srinivasan, postdoctoral scholar in the Huck Institutes of the Life Sciences. "Instead, we found that seven of the patient samples contained M. orygis. Six of these came from patients with extrapulmonary TB."They describe their findings in a paper published June 1 in As expected, most of the remainder of the sequences from the patients belonged to M. tuberculosis -- the TB bacterium that is generally thought to be transmitted only among humans."Our findings suggest that M. bovis might be uncommon in India, and that its detection may not be an adequate proxy for zoonotic TB infection in humans," said Srinivasan. "These data indicate that members of the TB complex other than M. bovis might be more prevalent in livestock in India."Kapur added that the operational definition of zoonotic TB should be broadened to include other MTBC subspecies capable of causing human disease."By 2035, the World Health Organization is aiming to reduce the incidence of tuberculosis by 90% as a part of its End TB Strategy," he said. "The increasing evidence supporting M. orygis endemicity in south Asia and the identification of M. tuberculosis in cattle highlight the importance of using a One Health approach, involving multisectoral collaboration across the veterinary and clinical sectors, to meet the WHO's goal in India."

Microbes

June 15, 2020

https://www.sciencedaily.com/releases/2020/06/200615115803.htm

Elasticity key to plants and animals' ability to sting

Kaare Hartvig Jensen and his colleagues at DTU Physics had repeated experiences where the small glass pipettes they use to extract fluid from plant cells broke upon contact with the cell wall. This annoyed the researchers and aroused their interest in similar pointed objects in nature that do not break when used. That includes thorns on plants such as cacti and nettles or the stings and spines of many insects, algae, hedgehogs, and other animals.

The idea of seeking inspiration in nature is not new to Kaare Hartvig Jensen, who belongs to a growing group of biomimetics researchers. They focus on exploring nature design to find inspiration for technical innovations related to, for example, tools and medical equipment.To acquire more knowledge on the subject, Kaare Hartvig Jensen and his colleagues conducted model experiments and collected data from more than 200 species, examining the design of various pointed objects in animals and plants. Their field of study was broad and included pointed parts of plants or animals used for very different purposes, for example for sticking to a surface, ingesting nourishment, or defence. The analysis furthermore included needles or stings on animals and plants which are made of vastly different materials and sizes, ranging from the smallest viruses and algae spikes, measuring just 50 nanometres, to the world's longest pointed part of an animal, the 2.5 metre narwhal tusk.The researchers also included the design of human-made pointed objects such as nails, syringe needles, and weapons (ancient spears and lances) up to six metres long.The large database allowed the researchers to identify how nature's pointy tools are designed to be both strong enough to penetrate human or animal skin, for example, and hard enough to ensure the tip does not break when coming into contact with the skin."Our results showed that there is a clear correlation between the length of a needle or sting and its diameter, both close to the tip and where it attaches to the plant or animal. In this way, both the necessary strength and elasticity of the tip can be ensured, whether on a nettle or a mosquito" says Kaare Hartvig Jensen."At the same time, it's clear that the pointy tools of nature are on the very edge of what is physically possible. And it's also clear that the designs are very similar, regardless of whether we're looking at the nanoscale spikes of a virus or a swordfish's 1.5 metre bill," says Kaare Hartvig Jensen.The findings from the new study have recently been published in the scientific journal The study also included human-made pointed objects that have already mimicked natural shapes to a large extent."This new knowledge of how to calculate the optimal design of a pointed object can in future be used to design, e.g., syringe needles to optimize the allocation of medication. Or in designing nails, enabling a reduction of material consumption without losing the necessary stability," says Kaare Hartvig Jensen.The researchers themselves have also used the results to redesign their glass pipettes so they no longer experience breakage when extracting fluid from plant cells.

Microbes

June 15, 2020

https://www.sciencedaily.com/releases/2020/06/200615115719.htm

Role of lipid rafts in virus infiltration

A cell's membrane acts as a natural shield, a fence around the cell that protects and contains it. It mediates processes that let nutrients through and let waste out, and it acts as a physical barrier to the entry of toxic substances and pathogens, like the viruses SARS-CoV-1 and SARS-CoV-2, the one that causes COVID-19.

Such pathogens, however, employ clever strategies to trick and penetrate the cell, thereby replicating themselves and infecting the human body. The virus deceives the membrane by exposing specific anti-receptors to which suitable cell's receptors normally bind. The virus tricks the receptors into believing that what's landing is something else, namely an affine ligand, something that is safe. Such a process activates and grows thickened zones along the cell membrane, or "lipid rafts," which are more likely to permit the virus to alter the cell's membrane, yielding its entry into the cell.New interdisciplinary research published in the "Although lipid rafts' influence on a cell's response to external agents has been deeply investigated, the physical components of what takes place during ligand-binding has not yet been fully understood," said Luca Deseri, research professor at the University of Pittsburgh's Swanson School of Engineering in the Mechanical Engineering and Materials Science Department, full professor and head of the graduate school in Engineering at DICAM-University of Trento in Italy, and corresponding author on the paper. "Our team used an interdisciplinary approach to better understand why active receptors tend to cluster on lipid rafts. More importantly, we confirm and predict the formation of the complex ligand receptors."Through the studies of how mechanical forces and biochemical interactions affect the cell membrane, this research sheds light on the way localized thickening across cell membranes is triggered by the formation of the ligand-receptor complex. The researchers concluded that the formation of ligand-receptor complexes could not take place in thinner zones of the cell membrane; the thickening of the cell membrane provides the necessary force relief to allow for configurational changes of the receptors, which then become more prone to ligand bindingUnderstanding the way viruses use lipid rafts to alter the cell wall could lead to new approaches to treat and prevent viruses, like the one that causes COVID-19, from spreading in the body.

Microbes

June 12, 2020

https://www.sciencedaily.com/releases/2020/06/200612111405.htm

Versatile symbionts: Reed beetles benefit from bacterial helpers through all life stages

Insects that feed only on plants have a number of challenges to overcome. But they also have some active helpers to assist them with the supply of important nutrients. So-called symbiotic microorganisms make essential amino acids, vitamins, and enzymes available and in this way supplement and enrich the limited diet of their host insects. Reed beetles with their semi-aquatic lifestyle also have such helpers that extend their range of available nutrients. Scientists at Johannes Gutenberg University Mainz (JGU) in collaboration with researchers at the Max Planck Institute for Chemical Ecology in Jena and partners in Hamburg and Japan have investigated the contributions that the symbiotic bacteria make to the unusual life cycle and diet of reed beetles. "Thanks to their symbiotic bacteria, reed beetles have been able to access new ecological niches. Although this means that the symbionts promote the ecological potential of their hosts, what is even more interesting is the fact that they can also restrict their adaptability," explained Professor Martin Kaltenpoth, head of the Department of Evolutionary Ecology at JGU.

Reed beetles are an ecologically unusual subgroup of the leaf beetle family and consist of around 165 species that live all or part of the time in water. The larvae of these reed beetles are aquatic and attach themselves to underwater plant roots from which they suck the sap as food. The adult beetles of most species live in vegetation above the water level and eat the leaves of plants such as grasses, sedges, and water lilies. In contrast with many other leaf beetles, the food sources of the larvae and the adult insects of the same species differ considerably. "The aquatic life stage of the larvae is highly unusual," stated Kaltenpoth, pointing out that the larvae even produce a cocoon under water, from which the mature beetles hatch. Since the early 1930s it has been known that reed beetles live in close symbiosis with bacteria that colonize blind sacs in the midgut of the larvae, but in the adult beetles they occupy the so-called Malpighian tubules, which are comparable to our kidneys. Scientists were also aware that without these symbionts the larvae would not be able to form a cocoon. However, how exactly the symbiotic bacteria contribute to the sustenance of their hosts has, as yet, remained a mystery.Using high-throughput sequencing techniques, the team led by Kaltenpoth sequenced the genetic material of the symbionts of 26 species of reed beetles from North America, Asia, and Europe. They reconstructed the entire genomes of the symbionts and were able to make predictions as to what these microbes actually do for their beetle hosts. It turns out that the bacteria can produce almost all of the essential amino acids, that is the ten protein components vital to life that the beetles cannot synthesize themselves. This is likely important for the larvae in particular, because the plant sap from roots does not supply sufficient amounts of amino acids -- and most importantly, not enough to build the protein-rich cocoon. "We know this form of cooperation in which most or all of the essential amino acids are supplied from many plant sap-feeding Hemiptera, for example aphids and cicadas, but this is uncommon in beetles," said the evolutionary biologist.A second aspect of the coexistence of adult reed beetles and bacteria is even more interesting. Some of the symbionts provide one or two enzymes that can break down pectins. Pectins are present in the cell walls of plants and are difficult to digest. They can be broken down by pectinases in order to contribute to the carbohydrate and energy supply of the herbivorous insects.The research team drew up a phylogenetic tree of the symbiotic bacteria to trace their evolutionary history. Interestingly, over the course of their evolution, the pectinases have disappeared from the symbiont genomes in four independent beetle lineages. Beetles that do not obtain pectinases through their symbiont are specialized to live on grasses and sedges, plants with low amounts of pectin. "These beetles have changed their food plant preferences. And because grasses and sedges only have small amounts of pectin in the cell wall, the pectinases provided by the symbionts were no longer useful and got subsequently lost," said Kaltenpoth. Beetles that continue to feed on water lilies, grass rush, or pondweed still have at least one pectinase.The results reveal that, on the one hand, symbionts can broaden the ecological potential of their host and enable it to adapt to a new niche. However, they also show that symbiotic microbes can restrict the selection of host plants if their enzymatic abilities are lost. "We think that the species of reed beetle that live on grasses and sedges can no longer return to consuming pectin-rich host plants," concluded Kaltenpoth.Reed beetles are among the few groups of beetles that have changed from a terrestrial to an aquatic life cycle. Symbiotic microorganisms have made a significant contribution to this move from land to water by supporting the nutrient supply of the larvae and adult beetles. However, as certain types of reed beetles no longer have pectinases available, they are also responsible for limiting the ecological environment their host can occupy.Professor Martin Kaltenpoth's research on the microbial ecology of reed beetles is being supported by an ERC Consolidator Grant, which he was awarded in 2018 to investigate aspects of symbiosis between beetles and bacteria. The biologist has been Professor of Evolutionary Ecology at Johannes Gutenberg University Mainz since 2015. He has recently been appointed new director of the Max Planck Institute for Chemical Ecology in Jena, where he will be setting up the new Department of Insect Ecology and Evolution from February 2021.

Microbes

June 12, 2020

https://www.sciencedaily.com/releases/2020/06/200612120148.htm

Novel mechanism triggers a cellular immune response

Viruses and other disease-causing microbes influence the type of immune response their hosts will develop against them. In some cases, the predominant response involves antibodies, proteins made by the immune system that specifically recognize parts of the invading microbe and mediate its destruction. In other cases, immune cells are trained to recognize the microbe and lead the attack against it.

Scientists have extensively investigated the mechanisms that lead to either an antibody or a cell-mediated response, and about 10 years ago, a novel signal was suggested as the trigger of a cell-mediated response. In a current study, Baylor researchers, Dr. William Decker, Dr. Matthew Halpert, Dr. Vanaja Konduri and their colleagues present comprehensive evidence that supports this phenomenon and propose a mechanism for its action.Research has shown that two factors related to microbes significantly affect the type of immune response that will predominate. On one hand are the microbial components (parts of proteins or genetic material, called pathogen-associated molecular patterns or PAMPs), and on the other is the location of the microbes, whether they tend to be inside or outside cells. Cells have means to recognize PAMPs ? some cellular proteins recognize PAMPs inside cells, while others detect PAMPs outside cells.Research on viruses has shown that when viral genetic material is detected inside cells, a cell-mediated immune response develops, while the detection of viral proteins outside the cell triggers antibody-mediated responses.The implementation of these immune responses involves cellular proteins called Pattern Recognition Receptors, or PRRs. Antigen-presenting cells, such as dendritic cells, are involved in the first steps of developing a specific immune response. During these first steps, antigen-presenting cells sample both the intracellular and extracellular environments by binding PAMPs to their PRRs. Recognition of a PAMP by a PRR turns on the danger alarm and alerts the rest of the immune system to the presence of a foreign microbial invader.In addition to these well-studied signals that mediate classic immune responses, Baylor researchers have proposed and demonstrated a different mechanism that directs the immune response toward a cellular type. This new mechanism also involves surveillance of both the intracellular and extracellular environments but by a different class of proteins called the Major Histocompatibility Complex, or MHC. MHC Class I binds protein fragments found inside of cells whereas MHC Class II binds protein fragments present on the outside of cells."This mechanism appears to take place mostly when a fulminant viral infection occurs," said Decker, associate professor of pathology and immunology and corresponding author of this work.When a virus avidly proliferates, parts of viral proteins can be found in abundance both inside and outside of cells. One possible outcome of this situation is that identical protein fragments bind to both MHC Class I and Class II proteins on antigen-presenting cells.When this occurs in conjunction with other inflammatory cues, "a response is triggered that promotes a cell-mediated immunity against that virus," said Decker, who also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "In this case, the response does not depend on any particular PAMP structure. Instead, it depends on the fact that the pieces of virus bound by MHC Class I and II have an identical amino acid sequence.""In this study, we defined experimental model systems that enabled us to study this specific mechanism without interference from classical mechanisms. We found ample evidence that supports the novel mechanism and described a large molecular sensor complex we propose plays a central role in comparing the amino acids sequences of intracellular and extracellular protein fragments," said Halpert, instructor of immunology at Baylor and first author of this work. "Although further research is needed, we anticipate that this novel mechanism has potential important clinical applications."Research has shown that naturally developed cell-mediated immunity against viral infections tends to confer protection that lasts longer than antibody-mediate immunity, which is induced by some vaccines. The authors propose that this novel mechanism that steers the immune response toward the cellular type offers a valuable opportunity to design vaccines that may induce more effective and durable cell-based immunity against current and future viral diseases as well as against cancers. Importantly, the Decker group is implementing this strategy in clinical trials, including a study for intent to treat pancreatic cancer (NCT04157127) due to open in June 2020 at Baylor St. Luke's Medical Center.This study was supported in part by the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP110545, a Reach Award from Alex's Lemonade Stand Childhood Cancer Foundation and NIH R01 AI127387. This project was also supported in part by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (AI036211, CA125123, and RR024574).

Microbes

June 11, 2020

https://www.sciencedaily.com/releases/2020/06/200611183908.htm

Researchers create new type of COVID-19 antibody test

As the COVID-19 pandemic continues with many thousands of new infections reported each day, there is a need for widely applicable surveillance testing to gain a better understanding of infection rates, especially the number of infections in people with mild or no symptoms, who can still be carriers. UNC School of Medicine scientists and colleagues developed a new kind of antibody test -- a simplified experimental assay that could be ramped up to test thousands of blood samples at labs that do not have the resources of commercial labs and large academic medical centers.

The researchers, who published their work in The RBD of the spike protein in SARS-CoV-2 is not shared among other known human or animal coronaviruses. Therefore, antibodies against this domain are likely to be highly specific to SARS-CoV-2, and so these antibodies reveal if an individual has been exposed to the virus that can cause COVID-19. Indeed, when the researchers tested blood collected from people exposed to other coronaviruses, none had antibodies to the RBD of SARS-CoV-2."Our assay is extremely specific for antibodies to the virus that causes COVID-19, which is not the case for some currently available antibody tests," said co-senior author Aravinda de Silva, professor of microbiology and immunology and member of the UNC Institute for Global Health and Infectious Diseases. "Our results strongly support the use of RBD-based antibody assays for population-level surveillance and as a correlate of the neutralizing antibody levels in people who have recovered from SARS-CoV-2 infections."First and co-senior author Prem Lakshmanane, PhD, assistant professor of microbiology and immunology at UNC, said, "We are now further streamlining our test into an inexpensive assay, so that instead of the test taking four to five hours to complete, our assay could be completed in about 70 minutes without compromising quality."During the UNC-Chapel Hill campus shutdown, Lakshmanane led a team of researchers including Ramesh Jadi, PhD, Bruno Segovia-Chumbez, and Rajendra Raut, PhD -- each designated as an emergency employee -- to develop the test from scratch. The team designed new antigens and used a large panel of SARS-CoV-2 patients and control human and animal samples. From day nine after the onset of symptoms and thereafter, the UNC assay allowed the researchers to accurately identify RBD-based antibodies to SARS-CoV-2.Coronavirus expert Ralph Baric, PhD, Kenan Distinguished Professor of Epidemiology at the UNC Gillings School of Global Public Health, developed an assay to measure neutralizing antibodies in clinical samples. Assays for measuring neutralizing antibodies take about three days to complete and often require special high-containment facilities necessary for safely working with infectious viruses. The de Silva Lab collaborated with David Martinez, PhD, in the Baric laboratory to test if the RBD-based antibody levels in patients correlated with levels of neutralizing antibodies found in the Baric assay."We observed a robust correlation between levels of RBD-binding antibodies and SARS-CoV-2 neutralizing antibodies in individual samples," Lakshmanane said. "This means our assay not only identifies people exposed to SARS-CoV-2, but it can also be used to predict levels of neutralizing antibodies and to identify potential donors for plasma therapy."The UNC-Chapel Hill researchers have received requests from scientists across the country and around the world for assistance with establishing this new assay within their research laboratories to monitor people for SARS-CoV-2 infection."We don't see our research as a means to replace commercial tests," said de Silva, a world-renowned arbovirus researcher. "Commercial tests are critical, especially for making decisions about the clinical management of individual patients. But it's too early in the pandemic to know if the commercial assays are suitable for identifying people who experienced very mild or no disease after infection or if the assays tell us anything about protective immunity, as researchers are still learning about this virus."He added, "It's important for researchers to stay engaged, to monitor antibody responses and other biological details, and to fine tune assays to meet the different needs of individual patients, the public health community, and vaccine developers."Other authors are Bruno Segovia-Chumbez, Ramesh Jadi, David R. Martinez, Rajendra Raut, Alena Markmann, Caleb Cornaby, Luther Bartelt, Susan Weiss, Yara Park, Caitlin E. Edward, Eric Weimer, Erin M. Scherer, Nadine Roupael, Sri Edupuganti, Daniela Weiskopf, Longping V. Tse, Y. Jacob Hou, David Margolis, Alessandro Sette, Matthew H. Collins, John Schmitz, and Ralph S. Baric.The University of North Carolina School of Medicine, the National Institutes of Health, and the Burroughs Welcome Fund Postdoctoral Enrichment Program funded this research.

Microbes

June 11, 2020

https://www.sciencedaily.com/releases/2020/06/200611152453.htm

A protein that helps to fight viruses can also block lung damage repair

Researchers at the Francis Crick Institute have found that a protein which is initially helpful in the body's immune response to a virus, can later interfere with the repair of lung tissue. The work, published in

When a virus infects the lungs, the body attempts to defend itself and fight off the infection. One defensive mechanism is the activation of a protein, called interferon lambda, which signals to surrounding lung tissue cells to switch on anti-viral defences.Interferon lambda is currently being investigated in clinical trials as a potential treatment for COVID-19, so understanding the biology underlying its anti-viral effects is important.The research team investigated the effects of this protein in the lab and found that if it is active for an extended period, it inhibits the repair of the lung tissue. This could prolong lung damage and increase the risk of subsequent bacterial infections.The Crick scientists observed that in mice with influenza, having increased levels of this protein in their lungs meant that their epithelial cells multiplied less. These cells make up the lining of the airspaces in the lung and need to multiply to replace damaged cells and repair damage. This was the case for mice treated with the protein experimentally and also mice that had produced the protein naturally, as a result of their response to the virus.Furthermore, cultures of human lung epithelial cells treated with this protein were also less able to grow.Andreas Wack, author and group leader of the Immunoregulation lab at the Crick says, "This is a really potent protein with many different functions. At the beginning of a viral infection, it is protective, triggering functions that help to fight the virus. However, if it remains in the tissue for too long, it could become harmful."This means, for any anti-viral treatment that uses this protein, there is a really careful balance that must be made. Clinicians should consider the timing of the treatment, the earlier this better, and the duration of treatment."While this research studied mice infected with influenza, the effects of this protein should be similar for other viruses that also cause lung damage, including coronavirus.The paper has been published alongside research from Harvard Medical School, which found that severe COVID-19 patients showed strong expression of this protein in their lungs.Jack Major, lead author and PhD student in the Immunoregulation lab at the Crick says, "Understanding how our bodies respond to infection has never been more important. Differences in our immune responses have huge implications for whether a treatment will work and what the side effects might be."Our results suggest that before pursuing treatment with interferon lambda, doctors should consider at what stage of the disease patients are, as treatment late in infection may increase the risk of prolonged damage."The Crick researchers will continue to study inflammatory pathways in lung infections, including infection with coronavirus.

Microbes

June 11, 2020

https://www.sciencedaily.com/releases/2020/06/200611152435.htm

Brain cells can harbor and spread HIV virus to the body

Researchers have found that astrocytes, a type of brain cell can harbor HIV and then spread the virus to immune cells that traffic out of the brain and into other organs. HIV moved from the brain via this route even when the virus was suppressed by combination antiretroviral therapy (cART), a standard treatment for HIV. The study, conducted by researchers at Rush University Medical Center in Chicago and published in

"This study demonstrates the critical role of the brain as a reservoir of HIV that is capable of re-infecting the peripheral organs with the virus," said Jeymohan Joseph, Ph.D., chief of the HIV Neuropathogenesis, Genetics, and Therapeutics Branch at NIH's National Institute of Mental Health, which co-funded the study. "The findings suggest that in order to eradicate HIV from the body, cure strategies must address the role of the central nervous system."HIV attacks the immune system by infecting CD4 positive (CD4+) T cells, a type of white blood cell that is vital to fighting off infection. Without treatment, HIV can destroy CD4+ T cells, reducing the body's ability to mount an immune response -- eventually resulting in AIDS.cART, which effectively suppresses HIV infections, has helped many people with HIV live longer, healthier lives. But some studies have shown that many patients receiving antiretroviral drugs also show signs of HIV-associated neurocognitive disorders, such as thinking and memory problems. Researchers know that HIV enters the brain within eight days of infection, but less is known about whether HIV-infected brain cells can release virus that can migrate from the brain back into the body to infect other tissues.The brain contains billions of astrocytes, which perform a variety of tasks -- from supporting communication between brain cells to maintaining the blood-brain barrier. To understand whether HIV can move from the brain to peripheral organs, Lena Al-Harthi, Ph.D., and her research team at Rush University Medical Center transplanted HIV-infected or noninfected human astrocytes into the brains of immunodeficient mice.The researchers found that the transplanted HIV-infected astrocytes were able to spread the virus to CD4+ T cells in the brain. These CD4+ T cells then migrated out of the brain and into the rest of the body, spreading the infection to peripheral organs such as the spleen and lymph nodes. They also found that HIV egress from the brain occurred, albeit at lower levels, when animals were given cART. When cART treatment was interrupted, HIV DNA/RNA became detectable in the spleen -- indicating a rebound of the viral infection."Our study demonstrates that HIV in the brain is not trapped in the brain -- it can and does move back into peripheral organs through leukocyte trafficking," said Dr. Al-Harthi. "It also shed light on the role of astrocytes in supporting HIV replication in the brain -- even under cART therapy."This information has significant implications for HIV cure strategies, as such strategies need to be able to effectively target and eliminate reservoirs of HIV replication and reinfection, Dr. Al-Harthi added."HIV remains a major global public health concern, affecting 30 to 40 million people across the globe. To help patients, we need to fully understand how HIV affects the brain and other tissue-based reservoirs," said May Wong, Ph.D., program director for the NeuroAIDS and Infectious Diseases in the Neuroenvironment at the NIH's National Institute of Neurological Disorders and Stroke, which co-funded the study. "Though additional studies that replicate these findings are needed, this study brings us another step closer towards that understanding."

Microbes

June 11, 2020

https://www.sciencedaily.com/releases/2020/06/200611133136.htm

Promising path found for COVID-19 therapeutics

A team of researchers at the University of Georgia has successfully demonstrated that a set of drug-like small molecules can block the activity of a key SARS-CoV-2 protein -- providing a promising path for new COVID-19 therapeutics.

Led by Scott Pegan, director of UGA's Center for Drug Discovery, the team was the first to evaluate the SARS-CoV-2 protein PLpro, known to be essential in other coronaviruses for both its replication and its ability to suppress host immune function."The PLpro from SARS-CoV-2 behaved differently than its predecessor that caused the SARS outbreak in 2003. Specifically, our data suggests that the SARS-CoV-2 PLpro is less effective at its immune suppression roles," said Pegan, professor of pharmaceutical and biomedical sciences in the College of Pharmacy. "This may be one of the underlying reasons why the current virus is not as fatal as the virus from the 2003 outbreak."The COVID-19 pandemic has affected more lives globally than the SARS outbreak of 2002-03, but its mortality rate is lower based on available numbers in early June. After the SARS outbreak, the World Health Organization reported 8,098 cases and 774 deaths -- a mortality rate of nearly 10%. According to Johns Hopkins University's COVID-19 dashboard on June 3, there were 6,435,453 confirmed cases globally and 382,093 deaths -- a mortality rate of nearly 6%.From an evolutionary standpoint, it's not good for a virus to be fatal for the host, and SARS in 2003 was particularly lethal, according to Pegan."The COVID-19 virus infects, but people don't run a fever before they are contagious, so there's a lot of focus on how virulence factors like PLpro have been modified by nature to give the virus a better chance, from its perspective, to coexist with us," he said. "Obviously we would not like for it to coexist, but COVID-19 seems to have solved the Goldilocks paradox of being in the right place at the right time and with the right infection level."Pegan collaborated with UGA scientists David Crich, Ralph Tripp and Brian Cummings to explore inhibitors designed to knock out PLpro and stop replication of the virus. They began with a series of compounds that were discovered 12 years ago and shown to be effective against SARS, but development was cut short since SARS had not reappeared."Obviously now we see the current coronavirus is probably going to be with us for a while -- if not this one, then probably other types of coronaviruses," Pegan said. "These compounds are a good starting point for therapeutic development. They have all the properties you would typically want to find in a drug, and they have a history of not being considered toxic."These compounds, naphthalene-based PLpro inhibitors, are shown to be effective at halting SARS-CoV-2 PLpro activity as well as replication. They offer a potential rapid development path to generating PLpro-targeted therapeutics for use against SARS-CoV-2."The kind of small molecules that we're developing are some of the first that are specifically designed for this coronavirus protease," Pegan said. "Up till now, most therapeutic work against SARS has targeted another virulence factor, C3Lpro. This is a great start with a different target. Our hope is that we can turn this into a starting point for creating a drug that we can get in front of the Food and Drug Administration."Four UGA labs, including students, brought their expertise to the project. Pegan's lab used modeling techniques to locate the differences between PLpro in the 2003 outbreak and the current outbreak, revealing the comparative weakness of the SARS-CoV-2 PLpro and suggesting potential inhibitors for testing.Medicinal chemist David Crich, professor and Georgia Research Alliance and David Chu Eminent Scholar in Drug Design, provided guidance on understanding the attributes of the inhibitors and is working to synthesize new compounds with improved properties.Testing of compounds against the virus was led by Ralph Tripp, an expert in respiratory viruses and related diseases who is Georgia Research Alliance Eminent Scholar of Vaccine and Therapeutic Studies and professor of infectious diseases in the College of Veterinary Medicine.Brian Cummings, professor and head of pharmaceutical and biomedical sciences, covered toxicology, ensuring that the compounds tested killed their intended targets without causing toxic effects for the host.The team's paper appears online in the journal

Microbes

June 11, 2020

https://www.sciencedaily.com/releases/2020/06/200611114529.htm

From bacteria to you: The biological reactions that sustain our rhythms

Every second of every day, countless biochemical reactions take place in our bodies' cells. The organization of this complex system is the result of billions of years of evolution, fine-tuning our functions since the first primordial organisms.

One such vital reaction is 'methylation', where a methyl group -- a carbon atom linked to three hydrogen atoms -- attaches itself to a target molecule. Methylation is involved in the regulation of everything from DNA to proteins, and it is so vital that it can be found in all living organisms.In a recent paper published in "Disfunction in methylation can cause any number of pathologies, from atherosclerosis to cancer," explains Fustin. "Previously we discovered that inhibiting methylation in mice and human cells disrupted their body clocks."Methylation and the circadian rhythm, he adds, are ancient mechanisms retained in many organisms from bacteria to humans. "So, we hypothesized that the link between the two was also ancient."The team began by collecting cells and tissue samples from different organisms and measuring their biological rhythms. On average, all organisms run on periods of 24 hours.The next step was to find out what happens when methylation is disrupted, and as anticipated, significant alterations in the circadian clock were detected in all cell types, including in plants and algae. However, cyanobacteria -- photosynthetic bacteria -- seemed relatively resistant."The methylation pathway in bacteria is slightly different from other organisms. But when an alternative compound inhibiting a different part of methylation was used, the circadian clock was indeed strongly affected there as well," Fustin continues.Applying their findings, the team then took a gene that is key in controlling bacterial methylation and introduced it into mouse and human cells. Exceptionally, the bacterial gene was able to protect the cells from the first methylation inhibition compound, with no alterations observed in circadian rhythms."Not only did we find the evolutionarily conserved link between two ancient biological pathways -- methyl metabolism and biological clocks -- but we also opened the door to a possible new treatment for methylation deficiencies," concludes Okamura."All organisms are more alike than you might think, and knowledge about how we evolved will allow us to better understand ourselves and the natural world."

Microbes

June 11, 2020

https://www.sciencedaily.com/releases/2020/06/200611094209.htm

How targeting killer T cells in the lungs could lead to immunity against respiratory viruses

A significant site of damage during COVID-19 infection is the lungs. Understanding how the lungs' immune cells are responding to viral infections could help scientists develop a vaccine.

Now, a team of researchers led by Salk Professor Susan Kaech has discovered that the cells responsible for long-term immunity in the lungs can be activated more easily than previously thought. The insight, published in the "Inside our lungs exist long-lived killer T cells that recognize specific viruses and protect us against re-infection, should we encounter the virus again. Our results have elucidated the manner by which these cells 'see' the virus upon re-infection and provide rapid immunity," says Kaech, director of Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis. "It also may help us understand long-term immunity as it relates to coronavirus."When we are first exposed to bacteria or viruses, such as influenza, one type of our immune cells, known as killer T cells, destroy infected cells to prevent the spread of the disease. Once the pathogen is cleared, these experienced killer T cells (also called killer "memory" T cells) remain in our body long-term, and "remember" previous invaders. These killer memory T cells enable our immune systems to more rapidly respond to a second attack and effectively provide long-term protective immunity against the invader, a fundamental concept behind vaccination.Scientists know a lot about how killer memory T cells get activated in lymphoid organs (such as lymph nodes). Immune messenger cells called dendritic cells present fragments of the virus to the killer memory T cell, similar to a handler presenting a scent to a hound, to license their killer function.But prior studies had not examined this interaction in vital organs, such as the lung. The lung is a frequent entry site for pathogens such as influenza and coronavirus, so the team set out to confirm whether this long-held dogma applied to killer memory T cells that reside in the lungs.Kaech and then-graduate student Jun Siong Low, first author of the paper, assumed that dendritic cells would be required to reactivate killer memory T cells to fight a second viral attack. So, they deleted various types of messenger cells one at a time in mice to see if the killer memory T cells would still recognize a second influenza infection. The researchers used a green florescent reporter protein to make the killer memory T cells glow if they recognized the virus. However, each time the researchers deleted a specific cell type, the killer memory T cells in the lungs continued to glow."At first, our results were disappointing because it didn't seem like our experiments were working; the killer memory T cells in the lungs continued to recognize the virus after the deletion of many different messenger cell types," says Low, now a postdoctoral fellow at the Institute for Research in Biomedicine (IRB) at the Università della Svizzera Italiana, in Switzerland. "Soon, we realized that these lung-resident killer memory T cells were special because they were not reliant on any single type of messenger cell. Instead, they could 'see' the second influenza infection through a variety of different messenger cells, including non-immune cells like lung epithelial cells, which was a remarkably exciting finding."In contrast, when the researchers examined the killer memory T cells in the lymph nodes -- glands that swell during infections -- they found that the killer memory T cells needed dendritic cells to recognize the second viral attack. This suggests that the anatomical location of the killer memory T cells dictates how they get reactivated, challenging the long-held dogma that killer memory T cells require dendritic cells for reactivation. The results help to reshape the paradigm of killer memory T cell activation.Because lung-resident killer memory T cells can be quickly reactivated by nearly any cell type at the site of pathogen entry, identifying vaccines that can create these lung-resident killer memory T cells will likely be critical for superior immunity to viral infections of the lungs."We will take this knowledge into our next study, where we will examine whether lung-resident killer memory T cells form after a coronavirus infection," says Kaech, holder of the NOMIS Chair. "Since not all infections induce killer memory T cells, we will determine if these cells form after a coronavirus infection and whether they can be protective against future coronavirus infections."Other authors included Yagmur Farsakoglu of Salk; Esen Sefik, Christian C.D. Harman, Ruaidhri Jackson, Justin Shyer, Xiaodong Jiang, and Richard A. Flavell of the Yale University School of Medicine; Maria Carolina Amezcua Vesely of the Universidad Nacional de Córdoba, in Argentina; Joseph B. Kelly of Stony Brook University and Linda S. Cauley of the University of Connecticut Health Center.The work was supported by the NOMIS Foundation; the National Institutes of Health (R01 AI123864, R37 AI066232, S10 OD020142, P30 CA106359-39); A*STAR National Science Scholarship PhD; a Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2BEP3_178444); a George E. Hewitt Foundation fellowship; the Howard Hughes Medical Institute; the Yale Center for Research Computing; the Yale Center for Genome Analysis; and the Waitt Advanced Biophotonics Core at Salk Institute for Biological Studies.

Microbes

June 10, 2020

https://www.sciencedaily.com/releases/2020/06/200610135051.htm

Can gut microbiome alter drug safety and efficacy?

Researchers at Princeton University have developed a systematic approach for evaluating how the microbial community in our intestines can chemically transform, or metabolize, oral medications in ways that impact their safety and efficacy.

The new methodology provides a more complete picture of how gut bacteria metabolize drugs, and could aid the development of medications that are more effective, have fewer side effects, and are personalized to an individual's microbiome.The study was published June 10 in the journal Previous studies have examined how single species of gut bacteria can metabolize oral medications. The new framework enables evaluation of a person's entire intestinal microbial community at once."Basically, we do not run and hide from the complexity of the microbiome, but instead, we embrace it," said Mohamed S. Donia, assistant professor of molecular biology. "This approach allows us to gain a holistic and more realistic view of the microbiome's contribution to drug metabolism."The team used the approach to evaluate the gut microbiome's effect on hundreds of common medications already on the market. The intestines are the primary region where pills and liquid medications are absorbed into the body.The researchers identified 57 cases in which gut bacteria can alter existing oral medications. Eighty percent of those had not been previously reported, emphasizing the potential of the method for revealing unknown drug-microbiome interactions.These alterations range from converting the medicine into an inactive state -- which can reduce its efficacy -- to converting the drug into a form that is toxic, potentially causing side effects.The framework could aid drug discovery by identifying potential drug-microbiome interactions early in development, informing formulation changes. The approach can also help during clinical trials to better analyze the toxicity and efficacy of drugs being tested.The intestines are home to hundreds of species of bacteria. The makeup of these communities -- what kinds of bacteria and how many of each species -- can vary considerably from person to person."This inter-person variability underscores why studying a single bacterial species makes it impossible to compare the microbiome's metabolism of drugs between individuals," Donia said. "We need to study the entire intestinal microbial community."The researchers found that some people's microbiomes had little effect on a given drug, while other microbiomes had a significant effect, demonstrating how important the community of bacteria -- rather than just single species -- is on drug metabolism."Everyone's microbiome is unique, and we were able to see this in our study," said Bahar Javdan, an M.D.-Ph.D. student in molecular biology and a co-first author on the study. "We observed three main categories -- drugs that were consistently metabolized by all the microbiomes in our study, drugs that were metabolized by some and not by others, and drugs that were not subject to any microbiome-derived metabolism."The methodological approach could be valuable for personalizing treatment to the microbiome of each patient. For example, the framework could help predict how a certain drug will behave, and suggest changes to the therapeutic strategy if undesired effects are predicted."This is a case where medicine and ecology collide," said Jaime Lopez, a graduate student in the Lewis-Sigler Institute for Integrative Genomics and a co-first author on the study, who contributed the computational and quantitative analysis of the data. "The bacteria in these microbial communities help each other survive, and they influence each other's enzymatic profiles. This is something you would never capture if you didn't study it in a community."The framework involves four steps for systematically evaluating the intestinal microbiome's effect on drugs.First, the researchers collected 21 fecal samples collected from anonymous donors and catalogued the bacterial species living in each individual. They found that the donors each had a unique microbial community living in their guts, and that the majority of these personalized communities can be grown in a lab culturing system that they developed.Next, they tested 575 FDA-approved drugs to see if they are chemically modified by one of the 21 cultured microbiomes, and then tested a subset of the drugs with all the cultured microbiomes. Here, they found microbiome-derived metabolites that had never been previously reported, as well as ones that have been reported in humans and associated with side effects but their origins were unknown. They found cases where all the donor microbiomes performed the same reactions on the drug, and others where only a subset did.Then they examined the mechanisms by which some of the modified drugs are altered by the cultured microbiomes. To understand exactly how the transformations occurred, they traced the source of the chemical transformations to particular bacterial species and to particular genes within those bacteria. They also showed that the microbiome-derived metabolism reactions that are discovered in this manner can be recapitulated in a mouse model, the first step in adapting the approach for human drug development.

Microbes

June 10, 2020

https://www.sciencedaily.com/releases/2020/06/200610112059.htm

Levels of SARS-CoV-2 RNA in sewage rose with COVID-19 cases in Dutch cities

Scientists have detected RNA from the new coronavirus, SARS-CoV-2, in the feces of people with COVID-19. So it stands to reason that the viral RNA could end up in city sewage, where it could be used to monitor prevalence of the disease. Now, researchers reporting in ACS'

Although infectious SARS-CoV-2 has been detected in stool samples, the virus spreads primarily through respiratory droplets when an infected person coughs, sneezes, laughs, speaks or breathes, according to recent studies. However, if the new coronavirus is present at high levels in sewage at treatment plants, it could pose risks to workers at the facilities. Gertjan Medema and colleagues wanted to see if they could detect SARS-CoV-2 in the domestic wastewater of cities in the early stages of the COVID-19 pandemic in the Netherlands. They also wanted to determine if levels of the virus's RNA correlated with the COVID-19 prevalence in each city. If so, sewage surveillance could be a helpful tool to monitor the circulation of SARS-CoV-2 in communities, especially since clinical testing likely underestimates the actual number of people infected with the virus.As the new coronavirus took hold in other parts of the world, the researchers collected sewage samples from wastewater treatment plants that serve six cities in the Netherlands to see if the virus could be detected in this way. Samples were taken 3 weeks before the first reported COVID-19 case in the Netherlands, and then at 1, 2.5 and 4 weeks after the first case. The team measured SARS-CoV-2 levels in the sewage using a technique called quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Then, the researchers correlated viral RNA levels with the number of COVID-19 cases reported in each city on the day of sampling. SARS-CoV-2 was undetectable in sewage from all cities 3 weeks before the first reported case, but as the outbreak progressed, the concentration of SARS-CoV-2 RNA in sewage increased with the number of reported COVID-19 cases in each city. Although more research is needed, this study and similar ones in different locations suggest that sewage surveillance of SARS-CoV-2 RNA could serve as a sensitive early warning system for increased virus circulation in the population, the researchers say.The authors acknowledge funding from the KWR Water Research Institute.

Microbes

June 10, 2020

https://www.sciencedaily.com/releases/2020/06/200610102730.htm

We're not all equal in the face of the coronavirus

Are there differences in immunity to the SARS-CoV-2 coronavirus between populations from different geographic regions?

Part of the answer to this question is to be found in the genomes of these groups of people and, more specifically, in the HLA genes responsible for the adaptive immune system. These genes are special in that they often differ between individuals. Thousands of possible variants (or alleles) have been identified, and not all of them are equally effective in fighting a new virus. The frequency of these alleles varies from one population to another due to past migrations and their adaptation to different environments.In a study to be published in the journal The genetic variability of immunity lies particularly in the genes of the HLA (Human Leukocyte Antigen) system. These genes produce HLA molecules that are positioned on the surface of cells. When a virus infects an organism, the invader's proteins are first cut into small fragments called peptides. The HLA molecules then bind on to these fragments and expose them to the surface of the cells, thereby triggering a cascade of immunity reactions designed to eliminate the virus.Alicia Sanchez-Mazas, a professor at the Anthropology Unit in UNIGE's Faculty of Sciences, explains: "From the 450 or so most common HLA molecules in hundreds of populations worldwide, we tried to identify the ones that are most strongly bound to the peptides of the new coronavirus." Over 7,000 peptides can be derived from all of the viral proteins of the coronavirus.The Geneva-based researcher and her international team used bioinformatic tools to perform the analysis. These can predict the binding affinities between the HLA molecules and the viral peptides on the basis of their physical and chemical properties. The scientists then turned to statistical models to compare the frequencies of these HLA variants in different human populations.The study classified the approximately 450 HLA molecules according to their relative capacity to bind the coronavirus peptides. It provides an essential reference inventory for identifying the genetic resistance or susceptibility of individuals to the virus. The study has also shown that the frequencies of these HLA variants differ significantly from one population to the next.José Manuel Nunes, a researcher at the Anthropology Unit -- and co-author of the article -- further explains: "We were surprised to find that Indigenous populations in America had both the highest frequencies of HLA variants that bind the most strongly to the peptides and the lowest frequencies of those that bind the least strongly." However, as José Manuel Nunes continues, we should not draw too hasty a conclusion from these results: "HLA molecules contribute to the immune response but they are far from being the only element that can be used to predict effective or ineffective resistance to a virus. This is also verified on the ground since America's Indigenous populations are apparently no less affected than others by COVID-19."In the same study, the authors also analysed the HLA-peptide bindings for all of the proteins of the six other viruses with pandemic potential (two other coronaviruses, three influenza viruses and the HIV-1 virus of AIDS). This showed that many HLA variants are capable of binding strongly to the peptides of all seven viruses studied. Others do the same for all respiratory-type viruses (coronavirus and influenza). This means that there are numerous "generalist" HLA molecules that are effective against a number of different viruses."The differences between populations observed in this study are actually differences in the frequencies of the generalist HLA variants that do not bind specifically to the coronavirus but also to other pathogens," points out professor Sanchez-Mazas. "This is what makes us think that the current differences between populations are the result of past adaptations to different pathogenic pressures, which is extremely informative for understanding the genetic evolution of our species."A logical follow-up to the study will be to determine precisely which coronavirus peptides are most strongly bound to the HLA molecules. It is these peptides that will have the highest chances of triggering an effective immune reaction. Identifying them will be vital for developing a vaccine.

Microbes

June 10, 2020

https://www.sciencedaily.com/releases/2020/06/200610094112.htm

COVID-19 false negative test results if used too early

In a new study, Johns Hopkins researchers found that testing people for SARS-CoV-2 -- the virus that causes COVID-19 -- too early in the course of infection is likely to result in a false negative test, even though they may eventually test positive for the virus.

A report on the findings was published in the May 13 issue of "A negative test, whether or not a person has symptoms, doesn't guarantee that they aren't infected by the virus," says Lauren Kucirka, M.D., Ph.D., M.Sc., obstetrics and gynecology resident at Johns Hopkins Medicine. "How we respond to, and interpret, a negative test is very important because we place others at risk when we assume the test is perfect. However, those infected with the virus are still able to potentially spread the virus."Kucirka says patients who have a high-risk exposure should be treated as if they are infected, particularly if they have symptoms consistent with COVID-19. This means communicating with patients about the tests' shortcomings. One of several ways to assess for the presence of SARS-CoV-2 infection is a method called reverse transcriptase polymerase chain reaction (RT-PCR). These tests rapidly make copies of and detect the virus's genetic material. However, as shown in tests for other viruses such as influenza, if a swab misses collecting cells infected with the virus, or if virus levels are very low early during the infection, some RT-PCR tests can produce negative results. Since the tests return relatively rapid results, they have been widely used among high-risk populations such as nursing home residents, hospitalized patients and health care workers. Previous studies have shown or suggested false negatives in these populations.For the new analysis, Johns Hopkins Medicine researchers reviewed RT-PCR test data from seven prior studies, including two preprints and five peer-reviewed articles. The studies covered a combined total of 1,330 respiratory swab samples from a variety of subjects including hospitalized patients and those identified via contact tracing in an outpatient setting.Using RT-PCR test results, along with reported time of exposure to the virus or time of onset of measurable symptoms such as fever, cough and breathing problems, the researchers calculated the probability that someone infected with SARS-CoV-2 would have a negative test result when they had the virus infection. In the published studies, health care providers collected nasal and throat samples -from patients and noted the time of virus exposure or symptom -onset and sample collection.From this data, the Johns Hopkins researchers calculated daily false-negative rates, and have made their statistical code and data publicly available so results can be updated as more data are published.The researchers estimated that those tested with SARS-CoV-2 in the four days after infection were 67% more likely to test negative, even if they had the virus. When the average patient began displaying symptoms of the virus, the false-negative rate was 38%. The test performed best eight days after infection (on average, three days after symptom onset), but even then had a false negative rate of 20%, meaning one in five people who had the virus had a negative test result."We are using these tests to rule out COVID-19, and basing decisions about what steps we take to prevent onward transmission, such as selection of personal protective equipment for health care workers," says Kucirka. "As we develop strategies to reopen services, businesses and other venues that rely on testing and contact tracing, it is important to understand the limitations of these tests."Ongoing efforts to improve tests and better understand their performance in a variety of contexts will be critical as more people are infected with the virus and more testing is required. The sooner people can be accurately tested and isolated from others, the better we can control the spread of the virus, the researchers say.Funding for the study was provided by the National Institute of Allergy and Infectious Diseases (R01AI135115 and T32DA007292), the Johns Hopkins Health System and the U.S. Centers for Disease Control and Prevention (NU2GGH002000).

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609144455.htm

First all-human mouse model of inherited prion disease

Human prion diseases include Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS). A new study in the open-access journal PLOS Biology reports a significant advance in the development of mouse models of human prion diseases. The study, by Emmanuel Asante and colleagues of the Medical Research Council Prion Unit at University College London, demonstrates spontaneous formation of disease-relevant, transmissible prion protein assemblies in mice bearing only human forms of the prion protein.

Prion diseases are due to the misfolding and cell-to-cell transmission of prion proteins, which go on to induce misfolding in the recipient cell. A significant feature of prion diseases is that different mutations give rise to diseases with strikingly different clinical manifestations. In studying these diseases, the faithful creation and propagation of distinct disease-specific strains has been essential to understanding transmission and pathogenesis.The prion diseases have largely been modeled in mice by introducing the gene for a prion protein bearing a disease-causing mutation. In previous studies the disease-causing mutations were not studied directly on the human prion protein gene, but instead the equivalent mutations were introduced into the mouse prion protein gene. This complication can cause formation and propagation of a strain of misfolded protein that is not found in human disease, thereby limiting our understanding of the human prion disease.To overcome this problem, the research team introduced a mutant human prion gene into mice carrying no mouse prion gene. As the mice aged over a year and a half, they spontaneously developed clusters of misfolded prion protein, something never observed before. When those clusters were used to inoculate younger mice carrying the same mutation, those mice developed misfolded prion protein clusters as well, directly demonstrating infectivity of the mutant protein, and mimicking the infectivity of patient-derived clusters of the same mutant protein. This is the first time that a spontaneous infection due entirely to mutant human prion protein has been shown in mice."This new model of an inherited prion disease is likely to provide important insights into human disease that we have previously been unable to study in the mouse," Dr Asante said, including events of disease initiation and spread that may inform development of therapies.

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609130016.htm

Methods to inactivate and safely study SARS-CoV-2

Detailed methods on how to perform research on SARS-CoV-2, the virus that causes COVID-19, including procedures that effectively inactivate the virus to enable safe study of infected cells have been identified by virologists in the Institute for Biomedical Sciences at Georgia State University.

The peer-reviewed paper on the novel coronavirus, published in the journal "Importantly, the study defines specific methods that fully inactivate the virus, that is make it non-infectious, in ways compatible with further scientific analysis," said Dr. Christopher Basler, professor in the Institute for Biomedical Sciences, director of the Center for Microbial Pathogenesis and a Georgia Research Alliance Eminent Scholar in Microbial Pathogenesis."This allows researchers to study the proteins and genes of the virus and how the infected host responds to infection outside of high containment. Confirming that such analyses can be done safely, with no risk of infection, will increase the rate of discovery about the virus and COVID-19."When the disease COVID-19 appeared in humans, virologists in Basler's lab, who study emerging pathogens, wanted to contribute to the effort to understand SARS-CoV-2 and develop medical countermeasures for the virus. Because the new pathogen causes serious disease for which there are no definitive treatments, biosafety level 3 (BSL3) facilities are required. It was also necessary to handle the virus with extra care because so little was known about it.To ensure the safety of the researchers and public, Basler and his team relied on biosafety experts who oversee the high-containment core at Georgia State. The experts created a plan that identified the optimal BSL3 facility on the university's Atlanta Campus for the work, developed rigorous training for the researchers (who were already experienced with high-containment work) and implemented procedures to enable safe and efficient work on SARS-CoV-2.Co-authors of the paper include Drs. Alexander Jureka and Jesus Silvas, postdoctoral research associates in Basler's lab in the Institute for Biomedical Sciences.

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609111050.htm

Parasitic fungi keep harmful blue-green algae in check

When a lake is covered with green scums during a warm summer, cyanobacteria -- often called blue-green algae -- are usually involved. Mass development of such cyanobacteria is bad for water quality because they can deprive the water of oxygen and produce toxins. But cyanobacteria can become sick, when for instance infected by fungal parasites. Researchers from the Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB) found out that these infections do not only kill cyanobacteria, they also make them easier to consume for their natural predators. Fungal parasites thus help to slow down the growth of blue-green algae.

Blue-green algal blooms are an increasing problem in waterbodies worldwide: Higher temperatures and growing nutrient loads lead to excessive growth of cyanobacteria. These mass developments affect water quality because many cyanobacteria produce toxins and reduce the oxygen concentration in the water, sometimes leading to death of fish and other aquatic organisms.The international team led by IGB found that algal growth can be controlled by parasitic fungi. "Many of these algae have long filamentous shapes or grow in colonies, which makes them difficult to be eaten by their natural predators," explains Dr. Thijs Frenken, first author of the study and researcher at IGB and the University of Windsor in Canada. Chytrids, a very common group of fungi, often infect cyanobacteria. The researchers have now shown that, in addition to infecting and killing algae, the fungi "chop" the algae into shorter pieces, making them easier to be eaten by small aquatic organisms. "We knew that fungal infections reduce the growth of cyanobacteria, but now we know that they also make them easier prey," says IGB researcher Dr. Ramsy Agha, head of the study.The researchers showed that in addition to "chopping" infected cyanobacteria filaments and making them more vulnerable to predation by small organisms in the water, zooplankton, parasitic fungi themselves serve as a valuable food supplement. Chytrid fungi contain various fats and oils that are an important part of the diet of small freshwater organisms and are not present in blue-green algae. Parasitic fungi therefore serve as an important dietary connection between different levels of aquatic food webs."These results show how parasites, although usually perceived as something bad, also have important positive effects on the functioning of aquatic ecosystems," says Professor Justyna Wolinska, head of the IGB research group Disease Evolutionary Ecology.

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609104302.htm

Immune cell discovery could improve the fight against hepatitis B

For the first time, researchers at The Westmead Institute for Medical Research (WIMR) have identified and described a new and unique subset of human cells that are involved in the immune response against hepatitis B (HBV) infection. The discovery could help develop new treatments for HBV and inform future vaccine design.

Currently, HBV vaccination protects against subsequent infection through immunological memory -- the vaccine 'trains' the immune system to eliminate pathogens when the body is exposed to the virus.For years, immunological memory was thought to be driven by B and T immune cell responses. Recent studies in mice have suggested that natural killer (NK) cells can also 'remember' viral infections, but it remained unknown whether this applied to human viral infections.Researchers from WIMR studied NK cells in humans who had been vaccinated against, or infected with HBV, and compared them to those who had not been exposed to the virus.The study, undertaken by PhD student Ratna Wijaya and led by Professor Golo Ahlenstiel and Dr Scott Read, describes for the first time, the presence of memory NK cells (mNKs) in humans following exposure to HBV.Professor Ahlenstiel said, "This finding is quite significant, as it helps our understanding of how the body fights against HBV following vaccination."Previously, we thought that the NK immune response was part of our 'innate' immune system. The innate immune system fights against all antigens (foreign bodies, such as viruses), rather than specifically targeting certain antigens. We have now confirmed that NK cells in humans can acquire an immunological 'memory', and specifically target HBV-infected cells in subsequent infections."HBV is a virus that attacks the liver. Although some individuals who are infected with HBV can eliminate the virus from their body, others, particularly those who are infected in childhood, may develop chronic infections."Vaccines have been vital in preventing the spread of HBV," Professor Ahlenstiel said."However, not everyone who is vaccinated will experience the same level of protection. A percentage of those vaccinated -- roughly five per cent -- will not develop immunity against HBV. This means they can still develop an infection, including a chronic infection."Without proper treatment, chronic HBV can lead to serious complications, including liver cancer, and liver cirrhosis with chronic liver failure. It is vital that we prevent such infections where we can."We hope that, through our discovery, we can harness the anti-viral properties of mNKs to develop new treatments and improve vaccines so that everyone is protected against this virus."

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609095112.htm

New antivirals for influenza and Zika

Leuven researchers have deployed synthetic amyloids to trigger protein misfolding as a strategy to combat the influenza A and Zika virus.

Amyloids are particular protein assemblies with properties similar to silk, that serve numerous functions. They also form upon protein misfolding resulting in protein inactivation.Frederic Rousseau and Joost Schymkowitz (VIB-KU Leuven) used these properties to invent synthetic amyloid peptides that can be tailored to switch-off the function of desired target proteins. These peptides, termed Pept-ins, already proved to be a valuable approach to tackle bacterial pathogens or slow down tumor growth. Now, Schymkowitz and Rousseau's team wanted to explore whether pept-ins could also be used to inactivate viral proteins and thereby interfere with viral replication.The researchers designed two Pept-ins encoding virus-specific amyloid sequences identified in influenza A and Zika virus proteins, respectively. In collaboration with Xavier Saelens (VIB-UGent) and Johan Neyts (KU Leuven), they tested the antiviral properties of these molecules."We found that each amyloid interferes with the replication of the corresponding virus," explains Emiel Michiels, PhD student in the lab of Schymkowitz and Rousseau. The effects turned out to be specific, adds Michiels: "For influenza A we show that our synthetic amyloid accumulates at the site of infection and interferes with viral replication in mice. The amyloid binds to the viral target protein, forcing the protein into a non-functional conformation. Influenza B is not affected by this Pept-in, highlighting the sequence specificity of this interaction."The new antiviral applications broaden the therapeutic potential of the Pept-in technology platform, which is explored by Aelin Therapeutics -- a spin-off company based on Schymkowitz and Rousseau's research. The researchers hope to investigate whether the same approach also work to target other types of viruses.

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609095106.htm

Re-trafficking proteins to fight Salmonella infections

When humans get infected by pathogenic bacteria, the body's immune system tries to eliminate the intruders. One way of doing this is by launching an inflammatory response -- a cascade of events that includes the expression of protective proteins, the activation of immune cells, and a process of controlled cell death when infected cells can't be saved.

Scientists including members of EMBL's Typas group, members of the group of EMBL alumnus Jeroen Krijgsveld at the German Cancer Research Center (DKFZ) in Heidelberg, and other collaborators have investigated how immune cells called macrophages respond to infection by the intracellular pathogen One of the unexpected findings of the study was that a well-known family of proteins called cathepsins move to a new location when cells get infected by Salmonella. Cathepsins are proteases -- proteins that break down other proteins. They're normally kept inside small subcellular structures known as lysosomes and have previously been implicated in promoting cell death, although the mechanism or any link between the process and bacterial infection were unknown. The scientists have now discovered that Salmonella causes newly produced cathepsins to accumulate in the nuclei of infected cells. The protein-degrading activity of cathepsins in the nucleus is then required to initiate an inflammatory form of programmed cell death.The new study shows the benefit of systematically following protein dynamics during infection, which can unravel new pathways and mechanisms the host uses to defend itself against pathogens.

Microbes

June 9, 2020

https://www.sciencedaily.com/releases/2020/06/200609095036.htm

National survey shows different bacteria on cell phones and shoes

The largest study of its kind in the U.S. shows thousands of different types of bacteria living on cell phones and shoes, including groups that have barely been studied by scientists.

"This highlights how much we have to learn about the microbial world around us," said David Coil, a researcher at the University of California, Davis Genome Center and first author on the paper, published June 9 in the journal In recent years scientists have started to better understand the communities of microbes, or microbiomes, found in basically every environment on the planet. We all carry around with us our own personal microbiome. While some of the microbes found in and on people can be harmful, the overwhelming majority of these microbes are harmless -- and some are even beneficial.In 2013-2014, Coil, with Russell Neches and Professor Jonathan Eisen of the UC Davis Genome Center, UC Davis graduate student and professional cheerleader Wendy Brown, Darlene Cavalier of Science Cheerleaders, Inc. and colleagues launched an effort to sample microbes from spectators at sporting events across the country. Volunteers swabbed cell phones and shoes from almost 3,500 people and sent the samples to the Argonne National Laboratory, University of Chicago, for processing.The researchers amplified and sequenced DNA from the samples and used the sequence information to identify major groups of bacteria in the samples.They found that shoes and cell phones from the same person consistently had distinct communities of microbes. Cell phone microbes reflected those found on people, while shoes carried microbes characteristic of soil. This is consistent with earlier results.The shoe microbes were also more diverse than those found on a person's phone.Although samples were collected at events across the country, the researchers did not find any conclusive regional trends. In some cases, there were big differences between samples collected at different events in the same city. In others, samples from distant cities looked quite similar.Surprisingly, a substantial proportion of the bacteria came from groups that researchers call "microbial dark matter." These microbes are difficult to grow and study in a lab setting and thus have been compared to invisible "dark matter" that astronomers think makes up much of the universe.Since they are so difficult to grow in a lab, these dark matter groups have only been discovered as scientists have used genetic sequencing technology to look for microbes in the world around us. Although many of the dark microbial groups come from remote or extreme environments, such as boiling acid springs and nutrient poor underground aquifers, some have been found in more mundane habitats, such as soil."Perhaps we were naïve, but we did not expect to see such a high relative abundance of bacteria from these microbial dark matter groups on these samples," Eisen said.A number of these dark microbe groups were found in more than 10 percent of samples, with two groups, Armatimonadetes and Patescibacteria, being found in almost 50 percent of swabs and somewhat more frequently in those from shoes than those from phones. Armatimonadetes is known to be widespread in soil."A remarkable fraction of people are traveling around with representatives from these uncultured groups on commonplace objects," Coil said.

Microbes

June 8, 2020

https://www.sciencedaily.com/releases/2020/06/200608192515.htm

Antibiotic used to treat tuberculosis could be surprise treatment for deadly superbug

USC researchers have discovered that an old antibiotic may be a powerful new tool against a deadly superbug, thanks to an innovative screening method that better mimics conditions inside the human body.

The antibiotic, rifabutin, is "highly active" in fighting multidrug-resistant Acinetobacter baumannii, a significant cause of life-threatening infections in medical facilities, researchers found.The study appears in "Rifabutin has been around for more than 35 years, and no one has ever studied it for Acinetobacter infections before," said first author Brian Luna, assistant professor of molecular microbiology and immunology at Keck School of Medicine of USC. "Going forward, we may find many new antibiotics that have been missed over the last 80 years because the screening tests used to discover them were suboptimal."Rifabutin is used to treat TB, especially in people with HIV/AIDS who can't tolerate a similar drug, rifampin. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.Until now, it hadn't been tried against Acinetobacter baumannii, which emerged during the Iraq War as a troop-killing superbug in military treatment facilities. Acinetobacter causes pneumonia, meningitis and bloodstream infections; it tends to strike patients requiring lengthy hospital stays and invasive devices like catheters and ventilators.Each year, Acinetobacter baumannii is responsible for about 2% of the 99,000 U.S. deaths from hospital-acquired infections, according to the Centers for Disease Control and Prevention.One reason rifabutin's superpower against superbugs was overlooked is because of current screening techniques, researchers said. Since the 1940s, new or existing antibiotics have been tested against bacteria grown in "rich culture media," a nutrient-packed broth or gel which speeds up the process by making the bacteria to grow rapidly."But bacteria grow very differently inside the human body," said Brad Spellberg, chief medical officer at the Los Angeles County-University of Southern California Medical Center and senior author of the study. So, the team designed a new type of "nutrient-limited" media that better mimics conditions inside the body. They hypothesized that the more realistic media might unmask antibiotics with hidden strengths.They found that rifabutin was vigorously active against Acinetobacter baumannii grown in the nutrient-limited media (as well as in animal tissue) but not effective against bacteria grown in the more commonly used media.The scientists discovered that rifabutin uses a unique, Trojan-horse strategy to trick the bacteria into actively importing the drug inside itself, bypassing the bacterial outer cell defenses. This "pump" that imports the drug is only active in the more human-like media. In traditional rich culture media, high levels of iron and amino acids suppress the pump's activity, researchers found."Rifabutin can be used immediately to treat such infections because it is already FDA-approved, cheap and generic, and on the market," Spellberg said. "But we would like to see randomized controlled human trials to prove its efficacy, so we know for sure one way or the other."In addition to Spellberg and Luna, other authors of the study are Bosul Lee, Amber Ulhaq, Jun Yan, Peggy Lu, Jiaqi Cheng, Travis Nielsen, Juhyeon Lim, Warisa Ketphan, Hyungjin Eoh, Rosemary She and Nicholas Skandalis, all of Keck; Malina Bakowski and Case McNamara of Calibr, Scripp Research Institute, in La Jolla; and Vincent Trebosc, Christian Kemmer, Sergio Lociuro and Glenn Dale of BioVersys AG in Basel, Switzerland.The study was supported by the National Institute of Allergy and Infectious Diseases (grants R01AI139052, R01AI130060 and R01AI117211 to BS), the Food and Drug Administration (BAA Contract HHSF223201710199C); and the Bill & Melinda Gates Foundation (OPP1107194).Disclosures: Luna, Spellberg and Nielsen own equity in ExBaq, which is developing rifabutin in an intravenous form for clinical use. USC has a financial interest in ExBaq. Dale, Trebosc, Kemmer and Lociuro own equity in BioVersys AG, a biopharmaceutical company.

Microbes

June 8, 2020

https://www.sciencedaily.com/releases/2020/06/200608132529.htm

New approach to reducing spread of mosquito-borne diseases

In the midst of the COVID-19 pandemic, another source of deadly and increasingly frequent disease outbreaks goes largely unnoticed by much of the world. Stanford researchers working in rural Kenya have identified the most productive breeding habitats for certain mosquitoes -- spreaders of untreatable viruses that sicken millions every year -- and revealed related community perspectives that could inform a solution. Their findings, published recently in

"Until everyone in the world has reliable access to safe piped water, low-tech community interventions that target unused water containers can lead to large reductions in human health risk from vector-borne diseases," said study senior author Desiree LaBeaud, a professor of pediatrics in the Stanford Medical School.Tiny as it may be, the Aedes aegypti mosquito poses an outsized threat to global public health. It transmits a host of viruses, such as dengue, chikungunya, Zika and yellow fever, for which there are no vaccines or therapies. Human victims suffer a range of symptoms that can include life-threatening encephalitis and hemorrhage or debilitating arthritis that persists for years. The past two decades have seen mosquito-caused disease outbreaks grow increasingly common and unpredictable.Countries on every continent except Antarctica have suffered a number of Aedes aegypti-spread virus outbreaks in recent years. These outbreaks have been underreported and infections often misdiagnosed in some African countries where public health efforts have long focused on night-time biting mosquitoes that transmit malaria. For example, the researchers found that residents in the study area had limited awareness of daytime-biting Aedes aegypti mosquitoes, and prioritized sleeping under bednets as a primary protection against mosquito-borne disease.Because of a lack of piped water, most people in the region obtain water from rainfall and wells or boreholes. Many people also leave stored water uncovered in various containers. The researchers surveyed hundreds of residents and measured mosquito abundance in buckets, jerry cans and other water-holding containers -- the most common breeding habitat for Aedes aegypti mosquitoes.More than half of the mosquitoes the researchers found were in tires, buckets and small containers with no immediate purpose, and nearly 40 percent of the mosquitoes they found were in buckets used for laundry. Although tires accounted for less than 1 percent of all containers, they contained nearly a third of the mosquitoes the researchers found.The findings suggest that reducing the number of unused containers lying around could be an efficient and effective means of mosquito control. Rather than try to cover or reduce the number of all water-holding containers or all containers of a certain type -- a complex and difficult approach for community members to sustain -- national and local health interventions should target the most likely mosquito-breeding habitats, such as laundry buckets and containers without a purpose, such as tires and trash, according to the researchers.Key to the effort is education and empowerment, as well as community events such as trash clean-ups to manage the accumulation of purposeless containers, according to the researchers who emphasize that women and children are the most likely agents of change. Women, who are most likely to collect and store water for households, can use simple nets, such as torn bednets, to cover laundry buckets. Children, who are generally more willing to engage with new ideas and take up new behaviors, can collect unused containers or turn unused tires into toys so they won't collect water for mosquito breeding."It sounds simple, but targeting specific containers by purpose can have a huge impact," said study lead author Jenna Forsyth, a postdoctoral research fellow at the Stanford Woods Institute for the Environment. "It's low cost, requires relatively little behavior change and can be scaled up easily."The research was funded by Stanford's Maternal & Child Health Research Institute, Center for African Studies and Emmett Interdisciplinary Program in Environment and Resources.

Microbes

June 8, 2020

https://www.sciencedaily.com/releases/2020/06/200608114658.htm

Many factors may contribute to steep, decades-long muskrat population drop

Muskrat populations declined sharply across North America over the last 50 years or so, and wildlife scientists have struggled to understand why. A Pennsylvania research team investigated whether pathogens, parasites, environmental contaminants and disease may be contributing to this decline.

Trappers saw steep declines in muskrat harvest throughout the animal's native range, with decreases exceeding 50% in some states, according to David Walter, Penn State adjunct assistant professor of wildlife ecology in the College of Agricultural Sciences. In Pennsylvania, for example, according to the state Game Commission, the muskrat harvest declined from 720,000 in 1983 to 58,295 in 2010."Some of that decline can be attributed to a reduction in trapping activity, but clearly the muskrat population is significantly smaller than it used to be," he said. "A number of theories to explain the widespread muskrat declines have been proposed, including habitat loss, predation, environmental contamination and diseases. In this study, we examine a number of those possibilities."To analyze trends in muskrat mortality, researchers pored over 131 articles, published from 1915 to 2019, from 27 U.S. states and nine Canadian provinces that contained information about muskrat exposure to diseases and contaminants and mortality events. Information collected from articles included; year of survey; location of survey; methodology; number of animals surveyed; pathogen or contaminant identities; and the presence or absence of associated disease, as evidenced by reported clinical signs or lesions.Among the common factors reported associated with muskrat infections or mortality in some cases were: viruses including canine distemper virus, rabies and Aleutian mink disease virus; a variety of fungal infections; ailments such as tularemia and Tyzzer's disease; cyanobacteria, possibly indicating the presence of toxic algae; parasites including protozoans, trematodes, cestodes, nematodes and ectoparasites such as ticks; toxins, including heavy metals from industrial discharges and lead from ammunition deposits; and agricultural-related contaminants including pesticides, herbicides and insecticides.Because of the wide range of differences in how the many authors had collected information about the factors in muskrat deaths, the researchers were unable to draw solid conclusions about which pathogens or contaminants may be contributing to declining muskrat populations. However, the findings, recently published in The study provides a baseline for understanding the potential role of pathogens, contaminants, parasites and diseases in the declines of muskrat populations across North America, noted lead researcher Laken Ganoe, who conducted the work as part of her master's degree thesis in wildlife and fisheries science."These data highlight critical knowledge gaps about muskrat health investigations and the circumstances surrounding and contributing to their decline that warrant future research efforts," she said. "There is still much that we do not understand about why muskrats are disappearing, and to protect them into the future we need to better understand not only disease dynamics, but how other factors such as ecosystem dynamics and climatic factors are playing a role as well."In earlier research, done in collaboration with the Pennsylvania Game Commission, Ganoe collected muskrat carcasses from Pennsylvania trappers and conducted necropsies to develop a snapshot of muskrat health and exposure in the state, which included tissue sample collection and screening for a wide variety of pathogens and contaminants. She also captured muskrats, surgically implanted them with radio transmitters and then tracked them using radio telemetry, to determine their movement patterns, home range size and survival.The Pennsylvania Game Commission and the U.S. Geological Survey funded this research.

Microbes

June 8, 2020

https://www.sciencedaily.com/releases/2020/06/200608092951.htm

Virus DNA spread across surfaces in hospital ward over 10 hours

Virus DNA left on a hospital bed rail was found in nearly half of all sites sampled across a ward within 10 hours and persisted for at least five days, according to a new study by UCL and Great Ormond Street Hospital (GOSH).

The study, published as a letter in the Instead of using the SARS-CoV-2 virus, researchers artificially replicated a section of DNA from a plant-infecting virus, which cannot infect humans, and added it to a millilitre of water at a similar concentration to SARS-CoV-2 copies found in infected patients' respiratory samples.Researchers placed the water containing this DNA on the hand rail of a hospital bed in an isolation room -- that is, a room for higher-risk or infected patients -- and then sampled 44 sites across a hospital ward over the following five days.They found that after 10 hours, the surrogate genetic material had spread to 41% of sites sampled across the hospital ward, from bed rails to door handles to arm rests in a waiting room to children's toys and books in a play area. This increased to 59% of sites after three days, falling to 41% on the fifth day.Dr Lena Ciric (UCL Civil, Environmental & Geomatic Engineering), a senior author of the study, said: "Our study shows the important role that surfaces play in the transmission of a virus and how critical it is to adhere to good hand hygiene and cleaning."Our surrogate was inoculated once to a single site, and was spread through the touching of surfaces by staff, patients and visitors. A person with SARS-CoV-2, though, will shed the virus on more than one site, through coughing, sneezing and touching surfaces."The highest proportion of sites that tested positive for the surrogate came from the immediate bedspace area -- including a nearby room with several other beds -- and clinical areas such as treatment rooms. On day three, 86% of sampled sites in clinical areas tested positive, while on day four, 60% of sampled sites in the immediate bedspace area tested positive.Co-author Dr Elaine Cloutman-Green (UCL Civil, Environmental & Geomatic Engineering), Lead Healthcare Scientist at GOSH, said: "People can become infected with Covid-19 through respiratory droplets produced during coughing or sneezing. Equally, if these droplets land on a surface, a person may become infected after coming into contact with the surface and then touching their eyes, nose or mouth."Like SARS-CoV-2, the surrogate we used for the study could be removed with a disinfectant wipe or by washing hands with soap and water. Cleaning and handwashing represent our first line of defence against the virus and this study is a significant reminder that healthcare workers and all visitors to a clinical setting can help stop its spread through strict hand hygiene, cleaning of surfaces, and proper use of personal protective equipment (PPE)."SARS-CoV-2 will likely be spread within bodily fluid such as cough droplets, whereas the study used virus DNA in water. More sticky fluid such as mucus would likely spread more easily.One caveat to the study is that, while it shows how quickly a virus can spread if left on a surface, it cannot determine how likely it is that a person would be infected.The study was supported by a funded UCL studentship in partnership with GAMA Healthcare and funding from the National Institute for Health Research.

Microbes

June 5, 2020

https://www.sciencedaily.com/releases/2020/06/200605145247.htm

Scientists develop unique polymer coating to tackle harmful fungi

Scientists from the University of Nottingham have developed a new way to control harmful fungi, without the need to use chemical bioactives like fungicides or antifungals.

Fungi cause diverse, serious societal and economic problems in the UK and globally. As well as causing fatal diseases in humans, fungi devastate food crops and spoil valuable products and materials. This has led to an antifungals/fungicide industry worth around $30bn globally.There are tight regulations around the use of fungicides and antifungals and there is also growing resistance of fungi to these agents.In a paper published today in Through previous work, the team found different combinations of fungicides which worked against fungi and also produced new understanding of preservative action against spoilage fungi.Although these advances meant less use of certain fungicides and chemicals, frequent tightening of regulations around usage are restricting the take up of technologies that still rely on bioactive agents, while spread of resistance worsens the problem. Consequently, potential bioactive-free technologies for combatting fungi are highly attractive to the industry.In this latest study, scientists show an alternative fungal control strategy, which doesn't have the 'killing affect' of fungicides.The team identified polymers that resist the attachment of different kinds of fungi, including pathogens. They screened hundreds of (meth)acrylate polymers in high throughput, identifying several that reduce attachment of the human pathogen Specific chemical features of the polymers were associated with weak fungal attachment. The materials were not toxic, supporting their passive utility. The team developed a formulation with the materials for inkjet-based 3D printing. Printed voice-prosthesis components showed up to 100% reduction in A similar approach against bacterial pathogens is also now being developed for a catheter coating to prevent infections in patients.Professor Simon Avery, from the School of Life Sciences at the University is a lead investigator on the paper, he said: "This is the first high-throughput study of polymer chemistries resisting fungal attachment."Our engagement to date with industry has highlighted a clear need for a new approach to control fungi and the major socioeconomic problems that they cause, as the value of existing strategies using bioactives (antifungals, fungicides) is eroded by growing resistance and regulations."This passive, anti-attachment technology that we have been developing addresses this need. We have been able to show that different polymers are effective in resisting diverse fungi that have broad socio-economic impacts."

Microbes

June 5, 2020

https://www.sciencedaily.com/releases/2020/06/200605132435.htm

New technique for engineering living materials and patterns

A new method for engineering living materials called 'MeniFluidics', made by researchers at the University of Warwick could see a transformation in tissue engineering and bio-art, as well as new ways to research cellular interactions.A bacterial biofilm patterned using MeniFluidics.

Living cells have many properties that non-living materials simply don't. The ability of controlling the emergent behaviours of cells and organising them into arbitrary patterns is a key step forward towards utilizing living materials, for uses such as organs on a chip. This is why new technologies are being developed to obtain such an ability.Physicists and biologists at the University of Warwick have teamed up to develop a new method for controlling cellular patterns, published in the journal ACS Synthetic Biology, titled 'Pattern engineering of living bacterial colonies using meniscus-driven fluidic channels', their new technique is called MeniFluidics.Grounded on the physics of meniscus generation, the researchers implemented structures into gel surfaces. Evaporation of water from gel materials lead to formation of open channels which can be used for guiding the direction and speed of cellular expansion.Dr Vasily Kantsler, from Department of Physics at the University of Warwick comments;"I believe that our catchy named (Menifluidics) technique will enable new opportunities in biophysical and biomedical research and applications such as antibiotic resistance and biofouling"Dr Munehiro Asally, from School of Life Science at the University of Warwick adds;"We hope MeniFluidics will be used widely by biophysics, microbiologists, engineers and also artists! As it is a simple and versatile method."

Microbes

June 5, 2020

https://www.sciencedaily.com/releases/2020/06/200605132429.htm

New killing mechanism discovered in 'game-changing' antibiotic

Scientists at the University of Liverpool and University of Utrecht have taken another step forward on their quest to develop a viable drug based on teixobactin -- a new class of potent natural antibiotic capable of killing superbugs.

Research published in Teixobactin was hailed as a 'game changer' when it was discovered in 2015 due to its ability kill multi-drug resistant bacterial pathogens such as MRSA without developing resistance. If made suitable for humans, it would mark the first new class of antibiotic drug for 30 years.Dr Ishwar Singh, an expert in Antimicrobial Drug Discovery and Development and Medicinal Chemistry at Liverpool's Centre of Excellence in Infectious Diseases Research, has led pioneering research over the past six years to develop teixobactin-based viable drugs. His research team was the first in the world to successfully create simplified synthetic forms of teixobactins which are effective in treating bacterial infections in mice.Dr Singh explained: "We know that the therapeutic potential of simplified synthetic teixobactins is immense, and our ultimate goal is to have a number of viable drugs from our synthetic teixobactin platform which can be used as a last line of defence against superbugs to save lives."In collaboration with NMR expert Professor Markus Weingarth at the University of Utrecht, the team used high resolution solid state NMR, and microscopy to show, for the first time, how synthetic teixobactins bind to lipid II (an essential component of the bacterial membrane) and kill the bacteria.Dr Singh said: "It had been assumed that teixobactins kill the bacteria by binding to bacterial cell wall bricks such as lipid II, but never shown until now. Our work also suggests that teixobactins kill the bacteria by capturing lipid II in massive clusters, a new killing mechanism, which we were excited to discover."Antimicrobial resistance (AMR) is a grave threat to human health and prosperity. The O'Neill report, commissioned by the UK government and published in 2016, suggests that without action AMR will cause the deaths of 10 million people a year by 2050. The development of new antibiotics is therefore a crucial area of study for scientists around the world.Dr Singh added: "A significant amount of work remains in the development of teixobactins as a therapeutic antibiotic for human use. Our study is a real step in right direction and opens the door for improving teixobactins and moving these toward clinic."So far, we have demonstrated that we can make teixobactins which are effective in treating infections from resistant bacterial pathogens and understand their binding modes in a bacterial membrane. Now we need to expand our understanding on mode of action on a library of teixobactins with different bacterial membranes to develop a catalogue of molecules which have potential to become a drug for human use."Dr Singh's work received funding support from the Department of Health and Social Care, UK and Rosetrees Trust.

Microbes

June 5, 2020

https://www.sciencedaily.com/releases/2020/06/200605121420.htm

Diet, gut microbes affect cancer treatment outcomes

What we eat can affect the outcome of chemotherapy -- and likely many other medical treatments -- because of ripple effects that begin in our gut, new research suggests.

University of Virginia scientists found that diet can cause microbes in the gut to trigger changes in the host's response to a chemotherapy drug. Common components of our daily diets (for example, amino acids) could either increase or decrease both the effectiveness and toxicity of the drugs used for cancer treatment, the researchers found.The discovery opens an important new avenue of medical research and could have major implications for predicting the right dose and better controlling the side effects of chemotherapy, the researchers report. The finding also may help explain differences seen in patient responses to chemotherapy that have baffled doctors until now."The first time we observed that changing the microbe or adding a single amino acid to the diet could transform an innocuous dose of the drug into a highly toxic one, we couldn't believe our eyes," said Eyleen O'Rourke, PhD, of UVA's College of Arts & Sciences, the School of Medicine's Department of Cell Biology and the Robert M. Berne Cardiovascular Research Center. "Understanding, with molecular resolution, what was going on took sieving through hundreds of microbe and host genes. The answer was an astonishingly complex network of interactions between diet, microbe, drug and host."Doctors have long appreciated the importance of nutrition on human health. But the new discovery highlights how what we eat affects not just us but the microorganisms within us.The changes that diet triggers on the microorganisms can increase the toxicity of a chemotherapeutic drug up to 100-fold, the researchers found using the new lab model they created with roundworms. "The same dose of the drug that does nothing on the control diet kills the [roundworm] if a milligram of the amino acid serine is added to the diet," said Wenfan Ke, a graduate student and lead author of a new scientific paper outlining the findings.Further, different diet and microbe combinations change how the host responds to chemotherapy. "The data show that single dietary changes can shift the microbe's metabolism and, consequently, change or even revert the host response to a drug," the researchers report in their paper published in In short, this means that we eat not just for ourselves but for the more than 1,000 species of microorganisms that live inside each of us, and that how we feed these bugs has a profound effect on our health and the response to medical treatment. One day, doctors may give patients not just prescriptions but detailed dietary guidelines and personally formulated microbe cocktails to help them reach the best outcome.Researchers have observed microbes and diet affecting treatment outcomes before. However, the new research stands out because it is the first time that the underlying molecular processes have been fully dissected.The researchers' new model is an extremely simplified version of the complex microbiome -- collection of microorganisms -- found in people. Roundworms serve as the host, and non-pathogenic E. coli bacteria represent the microbes in the gut. In people, the relationships among diet, microorganisms and host is vastly more complex, and understanding this will be a major task for scientists going forward.The research team noted that drug developers will need to take steps to account for the effect of diet and microbes during their lab work. For example, they will need to factor in whether diet could cause the microorganisms to produce substances, called metabolites, that could interfere or facilitate the effect of the drugs.The researchers suggest that the complexity of the interactions among drug, host and microbiome is likely "astronomical." Much more study is needed, but the resulting understanding, they say, will help doctors "realize the full therapeutic potential of the microbiota.""The potential of developing drugs that can improve treatment outcomes by modulating the microbes that live in our gut is enormous," O'Rourke said. "However, the complexity of the interactions between diet, microbes, therapeutics and the host that we uncovered in this study is humbling. We will need lots of basic research, including sophisticated computer modeling, to reveal how to fully exploit the therapeutic potential of our microbes."

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604152114.htm

Probiotics with top-performing Lactobacillus strains may improve vaginal health

Vaginal Lactobacillus bacterial strains largely perform better than strains currently used in probiotics for vaginal health, according to a study published June 4 in the open-access journal

Lactobacillus species in the lower reproductive tract of healthy women lower vaginal pH and protect against sexually transmitted infections. But women commonly suffer from bacterial vaginosis -- a disruption in the optimal Lactobacillus-dominated genital microbiota -- resulting in higher vaginal pH as well as vaginal discharge and inflammation. Bacterial vaginosis is associated with adverse pregnancy outcomes and a higher risk of sexually transmitted infections, including HIV. Although antibiotics are the standard of care for bacterial vaginosis, most cases recur within six months. Probiotics that include Lactobacilli have been explored to improve the durability of treatment, but the majority of products do not contain species commonly found in the vagina. There is an urgent need for the development of additional well-designed probiotics for vaginal health.In the new study, Passmore and colleagues compared 57 vaginal Lactobacillus strains from young African women to strains from commercial probiotic products for vaginal health. They analyzed their growth at varying pH values, ability to lower pH and produce antimicrobial products, pathogen inhibition, and susceptibility to antibiotics. Several vaginal strains exhibited better probiotic profiles than commercial strains, suggesting that they would be beneficial in the development of probiotic treatments for bacterial vaginosis. Moreover, whole-genome sequencing of the five best-performing vaginal strains revealed that they would likely be safe and not pose a risk of antimicrobial resistance. According to the authors, a wider range of well-characterized Lactobacillus-containing probiotics may improve treatment outcomes for bacterial vaginosis, and lower the risk of adverse pregnancy outcomes and sexually transmitted infections."Few probiotics aimed at promoting vaginal health contain Lactobacillus spp. that commonly colonize the lower genital tracts of African women," the authors add. "The discovery and use of novel vaginal probiotic strains in such women may improve the durability of bacterial vaginosis treatments and towards this end Happel et al. (2020) evaluated a multitude of vaginal Lactobacillus strains and identified some that should be tested as vaginal probiotics in clinical trials in Africa."

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604152102.htm

High-protein diets help insects to fight against blood parasites

Scientists studying insects have identified a crucial biological mechanism responsible for increasing their survival against blood parasites.

The finding, in which a high protein diet is linked to increased survival, could be a key stepping-stone to discovering how diet could help us fight parasitic blood infections.The study, led by researchers at Lancaster University and involving scientists in the UK and Australia looked at infected caterpillars. It revealed that those fed with high-protein diets survived for longer, and in greater numbers, than those with less protein in their food and that 'osmotic stress', not an enhanced immune system, is the reason behind the results.Dr Robert Holdbrook, who conducted much of the laboratory work as part of his PhD at Lancaster University, said: "Higher levels of protein and amino acids in the caterpillar's blood draws water out of the bacterial cells through osmosis. This process raises the concentration of solutes, which are basically all the other molecules needed by cells such as sugars and amino acids, within the bacteria. This higher solute concentration stresses the bacterial cells and slows down their growth."The researchers, who conducted their research on a species of caterpillar called the African cotton leafworm (Spodoptera littoralis) and the bacterium Xenorhabdus nematophila, believe this is the first time osmotic stress has been found to combat parasitic bacteria in the blood.How diet influences host-parasite interactions is still poorly understood, with most previous research attention focused on the effects of key nutrients on host immune systems.Dr Sheena Cotter of the University of Lincoln, who is a co-author of the paper, said: "Until now, we have generally assumed that when diet increases resistance to parasites it is because the diet boosts the host's immune system by, for example, providing the building blocks for more immune cells. But our study showed that when we increase protein in the diet, the bacteria grew less well, even when the insect's immune system was bypassed."Although this study focused on caterpillars and their parasites, the findings could offer a possible avenue of research on humans and blood conditions.Human blood exhibits natural variation in solute concentration, known as osmolality. But so far no clear link has been found between blood osmolality and parasite infections.Professor Kenneth Wilson of Lancaster University, who led the study, said: "We don't know yet whether these findings also apply to humans with parasites in their blood, for example malarial parasites or the bacteria that cause septicaemia, but this could be an exciting avenue for future research."

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604152041.htm

Foodborne illness? DNA-barcoded microbial spores can trace origin of objects

Every year, an estimated 48 million Americans get sick from foodborne illnesses, resulting in some 128,000 hospitalizations and 3,000 deaths, according to the U.S. Centers for Disease Control and Prevention. This public health problem is compounded by billions in economic damage from product recalls, highlighting the need to rapidly and accurately determine the sources of foodborne illnesses.

With the increasing complexity of global supply chains for the myriad foods available to consumers, however, the task of tracing the exact origin of contaminated items can be difficult.In a novel solution that can help determine the origin of agricultural products and other goods, Harvard Medical School scientists have developed a DNA-barcoded microbial system that can be used to label objects in an inexpensive, scalable and reliable manner.Reporting in The spores are derived from baker's yeast and a common bacterial strain used in a wide variety of applications, such as probiotic dietary supplements, and designed to be incapable of growing in the wild to prevent adverse ecological effects."Spores are in many ways an old-school solution and have been safely sprayed onto agricultural goods as soil inoculants or biological pesticides for decades. We just added a small DNA sequence we can amplify and detect," said study corresponding author Michael Springer, associate professor of systems biology in the Blavatnik Institute at HMS."We also worked hard to make sure this system is safe, using commonplace microbial strains and building in multiple levels of control," Springer added. "We hope it can be used to help solve problems that have enormous public health and economic implications."In recent years, scientists have learned a great deal about the interactions between microbes and their environments. Studies show that microbial communities in homes, on cell phones, on human bodies and more have unique compositions, similar to fingerprints. Attempts to use microbial fingerprints to identify provenance can be time consuming and are not easily scaled, however.The use of custom-synthesized DNA sequences as barcodes has been shown in principle to be effective for labeling food and other items. To be widely useful, DNA barcodes must be produced cheaply in large volumes, persist on objects in highly variable environments, and able to be reliably and rapidly decoded -- hurdles that have thus far not been overcome because DNA is fragile.In their study, Springer and colleagues set out to determine if DNA barcodes packaged within microbial spores, which can be sprayed onto crops and identified months later, could help solve these challenges.Many microorganisms, including bacteria, yeasts and algae, form spores in response to harsh environmental conditions. Analogous to seeds, spores allow microorganisms to remain dormant for extraordinarily long periods and survive extreme conditions such as high temperatures, drought and UV radiation.The research team created custom-made DNA sequences that they integrated into the genomes of the spores of two microorganisms -- Saccharomyces cerevisiae, also known as baker's yeast, and Bacillus subtilis, a common and widespread bacterium that has numerous commercial uses, including as a dietary probiotic, a soil inoculant and a fermenting agent in certain foods. These spores can be cheaply grown in the lab in large numbers.The synthetic DNA sequences are short and do not code for any protein product, and are thus biologically inert. Inserted into the genome in tandem, the sequences are designed so that billions of unique barcodes can be created.The team also ensured that DNA-barcoded spores could not multiply, grow and spread in the wild. They did so by using microbial strains that require specific nutritional supplementation and by deleting genes required for the spores to germinate and grow. Experiments involving from hundreds of millions to more than a trillion of the modified spores confirmed that they are unable to form colonies.To read the DNA barcodes, the researchers used an inexpensive CRISPR-based tool that can detect the presence of a genetic target rapidly and with high sensitivity. The technology, called SHERLOCK, was developed at the Broad Institute of MIT and Harvard, in a collaboration led by institute members James Collins and Feng Zhang."Spores can survive in the wild for an extremely long time and are a great medium for us to incorporate DNA barcodes into," said study co-first author Jason Qian, a graduate student in systems biology at HMS. "Identifying the barcodes is straightforward, using a plate reader and an orange plastic filter on a cell phone camera. We don't envision any challenges for field deployability."The team examined the efficacy of their barcoded microbial spore system through a variety of experiments.They grew plants in the laboratory and sprayed each plant with different barcoded spores. A week after inoculation, a leaf and a soil sample from each pot were harvested. The spores were readily detected, and even when the leaves were mixed together, the team could identify which pot each leaf came from.When sprayed onto grass outside and exposed to natural weather for several months, spores remained detectable, with minimal spread outside the inoculated region. On environments such as sand, soil, carpet and wood, the spores survived for months with no loss over time, and they were identified after disturbances such as vacuuming, sweeping and simulated wind and rain.Spores are very likely to persist through the conditions of a real-world supply chain, according to the researchers. As a proof-of-principle, they tested dozens of store-bought produce items for the presence of spores of Bacillus thuringiensis (Bt), a bacterial species that is widely used as a pesticide. They correctly identified all Bt-positive and Bt-negative plants.In additional experiments, the team built a 100-square-meter (~1000 square feet) indoor sandpit and found that the spread of spores was minimal after months of simulated wind, rain and physical disturbances.They also confirmed that spores can be transferred onto objects from the environment. Spores were readily identified on the shoes of people who walked through the sandpit, even after walking for several hours on surfaces that were never exposed to the spores. However, the spores could not be detected on these surfaces, suggesting that objects retain the spores without significant spread.This characteristic, the team noted, could allow spores to be used to determine whether an object has passed through an inoculated area. They tested this by dividing the sandpit into grids, each labeled with up to four different barcoded spores. Individuals and a remote-control car then navigated the sandpit.They found that they could identify the specific grids that the objects passed through with minimal false positives or negatives, suggesting a possible application as a complementary tool for forensics or law enforcement.The team also considered potential privacy implications, noting that existing technologies such as UV dyes, cell phone tracking and facial recognition are already widely used but remain controversial."As scientists, our charge is to solve scientific challenges, but at the same time we want to make sure that we acknowledge broader societal implications," Springer said. "We believe the barcoded spores are best suited for farming and industrial applications and would be ineffective for human surveillance." Regardless, the use and adoption of this technology should be done with a consideration of ethics and privacy concerns, the study authors said.The researchers are now exploring ways to improve the system, including engineering potential kill-switch mechanisms into the spores, finding ways to limit propagation and examining if the spores can be used to provide temporal information about location history."Outbreaks of harmful foodborne pathogens such as listeria, salmonella and E. coli occur naturally and frequently," Springer said. "Simple, safe synthetic biology tools and knowledge of basic biology allow us to create things that have a lot of potential in solving real world safety issues."Study co-first authors include Zhi-xiang Lu, Christopher Mancuso, Han-Ying Jhuang, Rocío del Carmen Barajas-Ornelas and Sarah Boswell.Additional authors include Fernando Ramírez-Guadiana, Victoria Jones, Akhila Sonti, Kole Sedlack, Lior Artzi, Giyoung Jung, Mohammad Arammash, Mary Pettit, Michael Melfi, Lorena Lyon, Siân Owen, Michael Baym, Ahmad Khalil, Pamela Silver and David Rudner.This work was supported by DARPA Biological Robustness in Complex Settings (grant HR001117S0029).

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604120540.htm

Deadly bacterial infection in pigs deciphered

New-born piglets often die painfully from infection with an intestinal bacterium. A team of researchers from 3 faculties at the University of Bern has now discovered how the bacterium causes fatal intestinal bleeding. They have thus made a breakthrough in veterinary research. Promising prospects for vaccinations and medications for use in humans too have now opened up.

The Clostridium perfringens bacterium is part of the large Clostridium genus which can cause various fatal illnesses in animals and humans. Clostridium infections are widespread. These bacteria are dangerous because they produce extremely strong poisons (toxins) which cause targeted damage to the host's cells. Dreaded diseases caused by Clostridium include botulism, tetanus, gas gangrene and intestinal infections, for example.Horst Posthaus's group in the Institute of Animal Pathology at the University of Bern is researching an intestinal infection in pigs which is caused by Clostridium perfringens. 10 years ago, they were already able to demonstrate that the toxin produced by the bacteria, the so-called beta toxin, kills vascular cells and thus causes bleeding in the piglet's intestine. Until now, however, it was unclear why the toxin attacked specifically these cells and not others. Julia Bruggisser, biochemist and doctoral student at the Institute of Animal Pathology, has now succeeded in solving the puzzle of this mechanism in an interdisciplinary collaboration between three faculties. The findings from the study have been published in the specialist journal Around five years ago, lab technician Marianne Wyder from the Institute of Animal Pathology came across a molecule called Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1 or even CD31 for short). It is located on the surface of various cells and plays a central role in intestinal bleeding in piglets. The actual role of the CD31 molecule is to regulate the interaction between inflammatory cells and the blood vessels. It predominantly occurs on cells which are located on the inside of blood vessels (so-called endothelial cells).During experiments, it was noticed that CD31 and the beta toxin are distributed almost identically on these cells. "Our project resulted from this initial observation," says Horst Posthaus. Julia Bruggisser from the Institute of Animal Pathology discovered that the toxin released by the bacteria in the intestine attaches to the CD31. Since the beta toxin numbers among the pore-forming toxins, it thus perforates the cell membrane and kills the endothelial cells. This results in damage to the vessels and bleeding in the intestine.Collaboration between multiple research groups at the University of Bern was essential for the success of the project. "For my research, I work in three laboratories at the university. Although it's challenging, I learn a lot and above all, it's fun," says Julia Bruggisser. In addition to animal pathology, she also works with groups headed by Britta Engelhardt (Theodor-Kocher Institute) and Christoph von Ballmoos (Department of Chemistry and Biochemistry). "They had the right questions and ideas. We were able to bring our know-how concerning CD31 and methods and reagents which we had developed into the study," says Britta Engelhardt. "It came together perfectly," adds Christoph von Ballmoos.The discovery makes it possible to develop better vaccines in order to prevent the fatal disease in pigs. "But we also want to investigate whether the attachment of beta toxin to CD31 on the endothelial cells also allows for the development of new forms of therapy, for vascular disease in humans, for example. We have already started more collaborations within the University of Bern to this end," says Horst Posthaus.This study was supported by the Swiss National Science Foundation (SNSF) and by a grant for international students at the University of Bern.

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604095651.htm

Scientists aim gene-targeting breakthrough against COVID-19

A team of scientists from Stanford University is working with researchers at the Molecular Foundry, a nanoscience user facility located at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), to develop a gene-targeting, antiviral agent against COVID-19.

Last year, Stanley Qi, an assistant professor in the departments of bioengineering, and chemical and systems biology at Stanford University and his team had begun working on a technique called PAC-MAN -- or Prophylactic Antiviral CRISPR in human cells -- that uses the gene-editing tool CRISPR to fight influenza.But that all changed in January, when news of the COVID-19 pandemic emerged. Qi and his team were suddenly confronted with a mysterious new virus for which no one had a clear solution. "So we thought, 'Why don't we try using our PAC-MAN technology to fight it?'" said Qi.Since late March, Qi and his team have been collaborating with a group led by Michael Connolly, a principal scientific engineering associate in the Biological Nanostructures Facility at Berkeley Lab's Molecular Foundry, to develop a system that delivers PAC-MAN into the cells of a patient.Like all CRISPR systems, PAC-MAN is composed of an enzyme -- in this case, the virus-killing enzyme Cas13 -- and a strand of guide RNA, which commands Cas13 to destroy specific nucleotide sequences in the coronavirus's genome. By scrambling the virus's genetic code, PAC-MAN could neutralize the coronavirus and stop it from replicating inside cells.Qi said that the key challenge to translating PAC-MAN from a molecular tool into an anti-COVID-19 therapy is finding an effective way to deliver it into lung cells. When SARS-CoV-2, the coronavirus that causes COVID-19, invades the lungs, the air sacs in an infected person can become inflamed and fill with fluid, hijacking a patient's ability to breathe."But my lab doesn't work on delivery methods," he said. So on March 14, they published a preprint of their paper, and even tweeted, in the hopes of catching the eye of a potential collaborator with expertise in cellular delivery techniques.Soon after, they learned of Connolly's work on synthetic molecules called lipitoids at the Molecular Foundry.Lipitoids are a type of synthetic peptide mimic known as a "peptoid" first discovered 20 years ago by Connolly's mentor Ron Zuckermann. In the decades since, Connolly and Zuckermann have worked to develop peptoid delivery molecules such as lipitoids. And in collaboration with Molecular Foundry users, they have demonstrated lipitoids' effectiveness in the delivery of DNA and RNA to a wide variety of cell lines.Today, researchers studying lipitoids for potential therapeutic applications have shown that these materials are nontoxic to the body and can deliver nucleotides by encapsulating them in tiny nanoparticles just one billionth of a meter wide -- the size of a virus.Now Qi hopes to add his CRISPR-based COVID-19 therapy to the Molecular Foundry's growing body of lipitoid delivery systems.In late April, the Stanford researchers tested a type of lipitoid -- Lipitoid 1 -- that self-assembles with DNA and RNA into PAC-MAN carriers in a sample of human epithelial lung cells.According to Qi, the lipitoids performed very well. When packaged with coronavirus-targeting PAC-MAN, the system reduced the amount of synthetic SARS-CoV-2 in solution by more than 90%. "Berkeley Lab's Molecular Foundry has provided us with a molecular treasure that transformed our research," he said.The team next plans to test the PAC-MAN/lipitoid system in an animal model against a live SARS-CoV-2 virus. They will be joined by collaborators at New York University and Karolinska Institute in Stockholm, Sweden.If successful, they hope to continue working with Connolly and his team to further develop PAC-MAN/lipitoid therapies for SARS-CoV-2 and other coronaviruses, and to explore scaling up their experiments for preclinical tests."An effective lipitoid delivery, coupled with CRISPR targeting, could enable a very powerful strategy for fighting viral disease not only against COVID-19 but possibly against newly viral strains with pandemic potential," said Connolly."Everyone has been working around the clock trying to come up with new solutions," added Qi, whose preprint paper was recently peer-reviewed and published in the journal The Molecular Foundry is a DOE Office of Science user facility.The Stanford team's work is supported by the Defense Advanced Research Projects Agency.

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604095628.htm

Small protein, big impact

Meningococci are bacteria that can cause life-threatening meningitis and sepsis. These pathogens use a small protein with a large impact: The RNA-binding protein ProQ is involved in the activation of more than 250 bacterial genes.

ProQ ensures that meningococci can better repair their DNA if damaged and it makes them resistant to oxidative stress. Both these factors contribute significantly to the bacteria's pathogenic properties.This was reported by research groups led by the Würzburg scientists Christoph Schoen and Jörg Vogel in the journal "We were surprised that a comparatively small protein can have such a great influence on bacterial gene regulation," says Christoph Schoen, professor at the Institute of Hygiene and Microbiology at Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany.ProQ only consists of about 120 amino acids. By comparison, many other proteins are usually made up of several hundred amino acids.The mini-protein belongs to the group of RNA-binding proteins. RNA molecules play an important role as regulators in many biological processes. They often perform their functions in combination with the binding proteins.ProQ is a key player in this respect: "In meningococci, the protein interacts with almost 200 different RNA molecules," says Jörg Vogel. "It binds to structured regions of the RNA and thus stabilises its binding partners."The researchers made the discovery using modern high-throughput processes. These methods were developed in Vogel's group at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg. Vogel is director of HIRI and heads the JMU Institute for Molecular Infection Biology.The scientists are interested in the processes in bacteria because they hope to find new targets for antibacterial agents. The pathways regulated by RNA and its binding proteins in particular offer a promising field of activity. "We hope to be able to disrupt the binding proteins in their function with small molecules and hence weaken the pathogens," explains Vogel.For two thirds of all RNAs in meningococci, the associated binding proteins have not yet been identified. This raises questions: Is it possible that the majority of RNAs does not need proteins to carry out their regulatory function in bacterial cells? And which processes are actually regulated by RNA-binding proteins?"This is what we would like to find out -- and meningococci are particularly well suited for this task because of their relatively small genome," says Schoen. "Our goal is to systematically identify the entire family of RNA-binding proteins in meningococci using established high-throughput methods."

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604111641.htm

A potential new weapon in the war against superbugs

University of Melbourne researchers are finding ways to beat dangerous superbugs with 'resistance resistant' antibiotics, and it could help in our fight against coronavirus (COVID-19) complications.

As bacteria evolve, they develop strategies that undermine antibiotics and morph into 'superbugs' that can resist most available treatments and cause potentially lethal infections.The Melbourne team has shown that a newly discovered natural antibiotic, teixobactin, could be effective in treating bacterial lung conditions such as tuberculosis and those commonly associated with COVID-19.Their work could pave the way for a new generation of treatments for particularly stubborn superbugs.Teixobactin was discovered in 2015 by a team led by Professor Kim Lewis at Northeastern University in Boston in 2015. His company is now developing it as a human therapeutic.The new University of Melbourne research, published in MRSA is among bacteria responsible for several difficult-to-treat infections in humans, particularly post-viral secondary bacterial infections such as COVID-19 chest infections and influenza.University of Melbourne Research Fellow in anti-infectives Dr Maytham Hussein and Associate Professor Tony Velkov's team synthesised an aspect of teixobactin to produce a compound that showed excellent effectiveness against MRSA, which is resistant to the antibiotic methicillin.Dr Hussein said that there was no way to stop bacteria like MSRA from developing resistance to antibiotics as it was part of its evolution. This made combatting it extremely challenging."The rise of multi drug-resistant bacteria has become inevitable," Dr Hussein said. "These bacteria cause many deadly infections, particularly in immunocompromised patients such as diabetic patients or those with cancers, or even elderly people with post-flu secondary bacterial infections."The University of Melbourne team is the first to find that teixobactin significantly suppressed mechanisms involved in resistance to vancomycin-based antibiotics that are recommended for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and MRSA-caused meningitis.The development could lead to new lung infection treatments and Associate Professor Velkov said it would greatly facilitate the pre-clinical development of teixobactin."Bacteria often develop resistance towards antibiotics within 48 hours after exposure," Associate Professor Velkov said. "The bacteria failed to develop resistance towards this compound over 48 hours."These novel results will open doors to develop novel antibacterial drugs for the treatment of multi-drug resistant Gram-positive infections -- bacteria with a thick cell wall -- which are caused by certain types of bacteria."

Microbes

June 4, 2020

https://www.sciencedaily.com/releases/2020/06/200604095640.htm

Study ties stroke-related brain blood vessel abnormality to gut bacteria

In a nationwide study, NIH funded researchers found that the presence of abnormal bundles of brittle blood vessels in the brain or spinal cord, called cavernous angiomas (CA), are linked to the composition of a person's gut bacteria. Also known as cerebral cavernous malformations, these lesions which contain slow moving or stagnant blood, can often cause hemorrhagic strokes, seizures, or headaches. Current treatment involves surgical removal of lesions when it is safe to do so. Previous studies in mice and a small number of patients suggested a link between CA and gut bacteria. This study is the first to examine the role the gut microbiome may play in a larger population of CA patients.

Led by scientists at the University of Chicago, the researchers used advanced genomic analysis techniques to compare stool samples from 122 people who had at least one CA as seen on brain scans, with those from age- and sex-matched, control non-CA participants, including samples collected through the American Gut Project. Initially, they found that on average the CA patients had more gram-negative bacteria whereas the controls had more gram-positive bacteria, and that the relative abundance of three gut bacterial species distinguished CA patients from controls regardless of a person's sex, geographic location, or genetic predisposition to the disease. Moreover, gut bacteria from the CA patients appeared to produce more lipopolysaccharide molecules which have been shown to drive CA formation in mice. According to the authors, these results provided the first demonstration in humans of a "permissive microbiome" associated with the formation of neurovascular lesions in the brain.Further analysis showed that some gut bacteria compositions could identify aggressive versus non-aggressive forms of the disease as well as those with recent symptomatic hemorrhages. Also, for the first time, they showed how combining gut bacteria data with results from blood plasma tests might help doctors better diagnose the severity of a brain disorder. The results, published in

Microbes

June 3, 2020

https://www.sciencedaily.com/releases/2020/06/200603132541.htm

'Poisoned arrow' defeats antibiotic-resistant bacteria

Poison is lethal all on its own -- as are arrows -- but their combination is greater than the sum of their parts. A weapon that simultaneously attacks from within and without can take down even the strongest opponents, from E. coli to MRSA (methicillin resistant

A team of Princeton researchers reported today in the journal Bacterial infections come in two flavors -- Gram-positive and Gram-negative -- named for the scientist who discovered how to distinguish them. The key difference is that Gram-negative bacteria are armored with an outer layer that shrugs off most antibiotics. In fact, no new classes of Gram-negative-killing drugs have come to market in nearly 30 years."This is the first antibiotic that can target Gram-positives and Gram-negatives without resistance," said Zemer Gitai, Princeton's Edwin Grant Conklin Professor of Biology and the senior author on the paper. "From a 'Why it's useful' perspective, that's the crux. But what we're most excited about as scientists is something we've discovered about how this antibiotic works -- attacking via two different mechanisms within one molecule -- that we are hoping is generalizable, leading to better antibiotics -- and new types of antibiotics -- in the future."The greatest weakness of antibiotics is that bacteria evolve quickly to resist them, but the Princeton team found that even with extraordinary effort, they were unable to generate any resistance to this compound. "This is really promising, which is why we call the compound's derivatives 'Irresistin,'" Gitai said.It's the holy grail of antibiotics research: an antibiotic that is effective against diseases and immune to resistance while being safe in humans (unlike rubbing alcohol or bleach, which are irresistibly fatal to human cells and bacterial cells alike).For an antibiotics researcher, this is like discovering the formula to convert lead to gold, or riding a unicorn -- something everyone wants but no one really believes exists, said James Martin, a 2019 Ph.D. graduate who spent most of his graduate career working on this compound. "My first challenge was convincing the lab that it was true," he said.But irresistibility is a double-edged sword. Typical antibiotics research involves finding a molecule that can kill bacteria, breeding multiple generations until the bacteria evolve resistance to it, looking at how exactly that resistance operates, and using that to reverse-engineer how the molecule works in the first place.But since SCH-79797 is irresistible, the researchers had nothing to reverse engineer from."This was a real technical feat," said Gitai. "No resistance is a plus from the usage side, but a challenge from the scientific side."The research team had two huge technical challenges: Trying to prove the negative -- that nothing can resist SCH-79797 -- and then figuring out how the compound works.To prove its resistance to resistance, Martin tried endless different assays and methods, none of which revealed a particle of resistance to the SCH compound. Finally, he tried brute force: for 25 days, he "serially passaged" it, meaning that he exposed bacteria to the drug over and over and over again. Since bacteria take about 20 minutes per generation, the germs had millions of chances to evolve resistance -- but they didn't. To check their methods, the team also serially passaged other antibiotics (novobiocin, trimethoprim, nisin and gentamicin) and quickly bred resistance to them.Proving a negative is technically impossible, so the researchers use phrases like "undetectably-low resistance frequencies" and "no detectable resistance," but the upshot is that SCH-79797 is irresistible -- hence the name they gave to its derivative compounds, Irresistin.They also tried using it against bacterial species that are known for their antibiotic resistance, including "Gonorrhea poses a huge problem with respect to multidrug resistance," said Gitai. "We've run out of drugs for gonorrhea. With most common infections, the old-school generic drugs still work. When I got strep throat two years ago, I was given penicillin-G -- the penicillin discovered in 1928! But for The researchers even got a sample of the most resistant strain of Without resistance to reverse engineer from, the researchers spent years trying to determine how the molecule kills bacteria, using a huge array of approaches, from classical techniques that have been around since the discovery of penicillin through to cutting-edge technology.Martin called it the "everything but the kitchen sink" approach, and it eventually revealed that SCH-79797 uses two distinct mechanisms within one molecule, like an arrow coated in poison."The arrow has to be sharp to get the poison in, but the poison has to kill on its own, too," said Benjamin Bratton, an associate research scholar in molecular biology and a lecturer in the Lewis Sigler Institute for Integrative Genomics, who is the other co-first-author.The arrow targets the outer membrane -- piercing through even the thick armor of Gram-negative bacteria -- while the poison shreds folate, a fundamental building block of RNA and DNA. The researchers were surprised to discover that the two mechanisms operate synergistically, combining into more than a sum of their parts."If you just take those two halves -- there are commercially available drugs that can attack either of those two pathways -- and you just dump them into the same pot, that doesn't kill as effectively as our molecule, which has them joined together on the same body," Bratton said.There was one problem: The original SCH-79797 killed human cells and bacterial cells at roughly similar levels, meaning that as a medicine, it ran the risk of killing the patient before it killed the infection. The derivative Irresistin-16 fixed that. It is nearly 1,000 times more potent against bacteria than human cells, making it a promising antibiotic. As a final confirmation, the researchers demonstrated that they could use Irresistin-16 to cure mice infected with This poisoned arrow paradigm could revolutionize antibiotic development, said KC Huang, a professor of bioengineering and of microbiology and immunology at Stanford University who was not involved in this research."The thing that can't be overstated is that antibiotic research has stalled over a period of many decades," Huang said. "It's rare to find a scientific field which is so well studied and yet so in need of a jolt of new energy."The poisoned arrow, the synergy between two mechanisms of attacking bacteria, "can provide exactly that," said Huang, who was a postdoctoral researcher at Princeton from 2004 to 2008. "This compound is already so useful by itself, but also, people can start designing new compounds that are inspired by this. That's what has made this work so exciting."In particular, each of the two mechanisms -- the arrow and the poison -- target processes that are present in both bacteria and in mammalian cells. Folate is vital to mammals (which is why pregnant women are told to take folic acid), and of course both bacteria and mammalian cells have membranes. "This gives us a lot of hope, because there's a whole class of targets that people have largely neglected because they thought, 'Oh, I can't target that, because then I would just kill the human as well,'" Gitai said."A study like this says that we can go back and revisit what we thought were the limitations on our development of new antibiotics," Huang said. "From a societal point of view, it's fantastic to have new hope for the future."

Microbes

June 3, 2020

https://www.sciencedaily.com/releases/2020/06/200603132514.htm

Respiratory virus builds 'doorbell' to trick its way into cells

New research from University of Alberta microbiologists has shed new light on how the respiratory syncytial virus (RSV) -- one of the most common viral infections -- breaks into our cells to cause infection.

In a study published in the journal "RSV kills between 150,000 and 200,000 people -- mainly children and infants -- every year worldwide," said Marchant, who is also the Canada Research Chair in Viral Pathogenesis and a member of the Li Ka Shing Institute of Virology and Alberta Respiratory Centre."This discovery identifies one of the first steps in RSV infection, and the hope is if we can block the interaction of the virus with the receptor, we may be able to stop the infection from happening."Currently, there is no vaccine or therapeutics to treat RSV, and nothing on the horizon, Marchant said. RSV most often affects infants and young children, infecting the lungs and airways. In fact, some experts estimate that almost all children have been infected with RSV by the time they reach the age of three. It's the leading cause of infant hospitalization in the world and the second leading cause of infant mortality next to malaria.RSV is unique because it lies on top of the surface of a cell for hours before gaining access and infecting it, unlike other viruses such as influenza, which can break into a cell within minutes by fusing with it.In 2011, Marchant led a team that discovered that a receptor within the cell called nucleolin played a role in facilitating RSV's entry into the cell -- RSV bound itself to the receptor and piggybacked in. However, it was unknown how or why nucleolin "came to the door" in the first place.In the new study, Marchant's team found that RSV bound itself to a second receptor, called IGF1R, and a gene protein called PKC-zeta, using both to create a signal, or "doorbell," to call nucleolin to the surface of the cell, where the virus awaits. Once nucleolin arrives at the surface, RSV binds itself to it to enter and infect the cell, like an imposing and uninvited guest."Essentially, RSV has evolved to exploit a normal, healthy function within the cell," said Marchant. "It raises some interesting questions, like 'Did the virus evolve to bind to IGF1R first or did it evolve to bind to the nucleolus first?' I think we'll be exploring this more over the next few years."Marchant said he hopes this discovery can lead to new treatments in the future, though he noted that developing a viable treatment for RSV is still years away."We have a number of different therapeutic candidates that we're working on in the lab to try to help move these forward into the clinic, such as blocking other receptors that are downstream from nucleolin in the process," he said. "But we don't yet know if there are side-effects to inhibiting those other signals, so we've got to look into that."Marchant's research was supported through grants from the Women and Children's Health Research Institute, Li Ka Shing Institute of Virology, The Lung Association, the Canadian Lung Association and the Canadian Institutes of Health Research.

Microbes

June 3, 2020

https://www.sciencedaily.com/releases/2020/06/200603130021.htm

Atomic blueprint of 'molecular machine' reveals role in membrane protein installation

Van Andel Institute scientists have revealed the first known atomic structure of a "molecular machine" responsible for installing critical signaling proteins into cellular membranes.

The findings, published today in "Determining precisely how proteins are assembled and function is central to understanding how the body works on the most basic level," said VAI Professor Huilin Li, Ph.D., leader of the Institute's Structural Biology Program and the study's senior author. "Our findings provide a map for future studies that one day could be translated into ways to combat disease."Proteins are the molecular workhorses of the body, responsible for carrying out nearly every biological function. Roughly one-third of proteins are membrane proteins, whose jobs include relaying information to and from cells, and transporting ions and molecules through the cell membrane, among other vital tasks. These important roles make them popular marks for therapy -- more than half of the medications on the market target membrane proteins as a way to treat disease.The endoplasmic reticulum membrane complex, or EMC, is embedded in the endoplasmic reticulum, a system of membranes within cells that plays a part in the creation, editing and transport of proteins. When the EMC's machinery breaks down, protein production can go awry, resulting in misshapen proteins that cannot do their jobs properly. For example, problems with the EMC are directly associated with cystic fibrosis, a genetic lung disease caused by improper assembly of a protein called CFTRDF508.Using the Institute's powerful cryo-electron microscopes (cryo-EM), Li and his colleagues visualized the EMC of a common yeast strain. Yeast are commonly used models in biology because they have many of the same molecular systems as humans but are much simpler to study.They found that the yeast EMC is larger than previously thought, containing eight protein subunits instead of six. Additionally, the core of the EMC resembles a protein that performs a similar function as the EMC in bacteria, suggesting that the EMC in eukaryotic organisms like mammals may have arisen from bacterial systems.Collectively, the findings shed light on how membrane proteins become established in membranes and how they change from their unstructured form to their functional form once there -- processes that have not been well understood until now.

Microbes

June 3, 2020

https://www.sciencedaily.com/releases/2020/06/200603100454.htm

Bacteria fed by algae biochemicals can harm coral health

Though corals worldwide are threatened due to climate change and local stressors, the front lines of the battle are microscopic in scale. Under stress, many reefs that were formerly dominated by coral are shifting to systems dominated by turf and fleshy algae. A new study, published in

All plants and animals are associated with communities of viruses and microbes -- their microbiome -- that interact via a suite of chemicals produced by their metabolism, termed metabolites. The new study, largely conducted at SDSU, investigated the role of each component, host organisms, viruses, bacteria, and metabolites, in coral-turf algal interactions. The researchers gathered data on genes, proteins and metabolic products associated with corals and algae on a reef and directly looked at the bacteria and viruses under a microscope."We found that when coral interacts with turf algae on a reef, there is a unique chemical and bacterial community that forms at the interface between these two organisms, an emergent microbiome," said Ty Roach, postdoctoral researcher at the Hawai'i Institute of Marine Biology in the UH M?noa School of Ocean and Earth Science and Technology and co-lead author of the study. "This interface community is made up of larger bacterial cells that use energy at a faster rate. Our data suggest that this change in bacterial size and energy use, which can negatively affect coral, is driven by a change in which types of bacteria dominate the microbiome.""Our chemical analysis indicates this change is driven by bacteria that feed on algal-derived biochemicals, a phenomenon we call the Algal Feeding Hypothesis," said co-lead author Mark Little, doctoral candidate. "Interestingly, these changes in bacterial groups and their energy use, which comes from feeding on specific chemicals, are similar to changes seen in the human gut, with dominant bacteria linked to obesity."Coral reefs are valued for their cultural and ecological importance, providing protection against storms and waves, and serve as reservoirs of biodiversity. Restoring coral cover and building reef resilience provides the foundation essential to a functional and healthy reef ecosystem, which is critical for the surrounding community."This highlights the fact that many ecological interactions between organisms are actually mediated by viruses and bacteria," said Forest Rohwer, biology professor and senior author of the study. "This provides opportunities to engineer probiotics to alleviate the effects of stressors on corals."The research team plans to use the insight gained from this study to design and test probiotic blends for use on corals. In this way, they aim to utilize personalized medicine techniques to help corals gain an ecological advantage over competitors such as harmful algae.

Microbes

June 2, 2020

https://www.sciencedaily.com/releases/2020/06/200602183403.htm

Antibiotic-destroying genes widespread in bacteria in soil and on people

The latest generation of tetracyclines -- a class of powerful, first-line antibiotics -- was designed to thwart the two most common ways bacteria resist such drugs. But a new study from researchers at Washington University in St. Louis and the National Institutes of Health (NIH) has found that genes representing yet another method of resistance are widespread in bacteria that live in the soil and on people. Some of these genes confer the power to destroy all tetracyclines, including the latest generation of these antibiotics.

However, the researchers have created a chemical compound that shields tetracyclines from destruction. When the chemical compound was given in combination with tetracyclines as part of the new study, the antibiotics' lethal effects were restored.The findings, available online in "We first found tetracycline-destroying genes five years ago in harmless environmental bacteria, and we said at the time that there was a risk the genes could get into bacteria that cause disease, leading to infections that would be very difficult to treat," said co-senior author Gautam Dantas, PhD, a professor of pathology and immunology and of molecular microbiology at Washington University School of Medicine in St. Louis. "Once we started looking for these genes in clinical samples, we found them immediately. The fact that we were able to find them so rapidly tells me that these genes are more widespread than we thought. It's no longer a theoretical risk that this will be a problem in the clinic. It's already a problem."In 2015, Dantas, also a professor of biomedical engineering, and Timothy Wencewicz, PhD, an associate professor of chemistry in Arts & Sciences at Washington University, discovered 10 different genes that each gave bacteria the ability to dice up the toxic part of the tetracycline molecule, thereby inactivating the drug. These genes code for proteins the researchers dubbed tetracycline destructases.But they didn't know how widespread such genes were. To find out, Dantas and first author Andrew Gasparrini, PhD -- then a graduate student in Dantas' lab -- screened 53 soil, 176 human stool, two animal feces, and 13 latrine samples for genes similar to the 10 they'd already found. The survey yielded 69 additional possible tetracycline-destructase genes.Then they cloned some of the genes into E. coli bacteria that had no resistance to tetracyclines and tested whether the genetically modified bacteria survived exposure to the drugs. E. coli that had received supposed destructase genes from soil bacteria inactivated some of the tetracyclines. E. coli that had received genes from bacteria associated with people destroyed all 11 tetracyclines."The scary thing is that one of the tetracycline destructases we found in human-associated bacteria -- Tet(X7) -- may have evolved from an ancestral destructase in soil bacteria, but it has a broader range and enhanced efficiency," said Wencewicz, who is a co-senior author on the new study. "Usually there's a trade-off between how broad an enzyme is and how efficient it is. But Tet(X7) manages to be broad and efficient, and that's a potentially deadly combination."In the first screen, the researchers had found tetracycline-destructase genes only in bacteria not known to cause disease in people. To find out whether disease-causing species also carried such genes, the scientists scanned the genetic sequences of clinical samples Dantas had collected over the years. They found Tet(X7) in a bacterium that had caused a lung infection and sent a man to intensive care in Pakistan in 2016.Tetracyclines have been around since the 1940s. They are one of the most widely used classes of antibiotics, used for diseases ranging from pneumonia, to skin or urinary tract infections, to stomach ulcers, as well as in agriculture and aquaculture. In recent decades, mounting antibiotic resistance has driven pharmaceutical companies to spend hundreds of millions of dollars developing a new generation of tetracyclines that is impervious to the two most common resistance strategies: expelling drugs from the bacterial cell before they can do harm, and fortifying vulnerable parts of the bacterial cell.The emergence of a third method of antibiotic resistance in disease-causing bacteria could be disastrous for public health. To better understand how Tet(X7) works, co-senior author Niraj Tolia, PhD, a senior investigator at the National Institute of Allergy and Infectious Diseases at the NIH, and co-author Hirdesh Kumar, PhD, a postdoctoral researcher in Tolia's lab, solved the structure of the protein."I established that Tet(X7) is very similar to known structures but way more active, and we don't really know why because the part that interacts with the tetracycline rings is the same," Kumar said. "I'm now taking a molecular dynamics approach so we can see the protein in action. If we can understand why it is so efficient, we can design even better inhibitors."Wencewicz and colleagues previously designed a chemical compound that preserves the potency of tetracyclines by preventing destructases from chewing up the antibiotics. In the most recent study, co-author Jana L. Markley, PhD, a postdoctoral researcher in Wencewicz's lab, evaluated that inhibitor against the bacterium from the patient in Pakistan and its powerful Tet(X7) destructase. Adding the compound made the bacteria two to four times more sensitive to all three of the latest generation of tetracyclines."Our team has a motto extending the wise words of Benjamin Franklin: 'In this world nothing can be said to be certain, except death, taxes and antibiotic resistance,'" Wencewicz said. "Antibiotic resistance is going to happen. We need to get ahead of it and design inhibitors now to protect our antibiotics, because if we wait until it becomes a crisis, it's too late."

Microbes

June 2, 2020

https://www.sciencedaily.com/releases/2020/06/200602110142.htm

More efficient biosolar cells modelled on nature

Potential sources of renewable energy include protein complexes that are responsible for photosynthesis. However, their efficiency in technical applications still leaves much to be desired. For example, they cannot convert green light into energy. A research team has successfully closed this so-called green gap by combining a photosynthesis protein complex with a light-collecting protein from cyanobacteria.

Biosolar cells are an innovative concept for converting sunlight into electrical energy. They are manufactured using biological components from nature. At their core are so-called photosystems: large protein complexes that are responsible for energy conversion in plants, algae and cyanobacteria. Photosystem II, PSII for short, plays a central role in the process, because it can use water as an electron source for the generation of electricity."However, as unique as PSII is, its efficiency is limited, because it can use merely a percentage of the sunlight," explains Professor Marc Nowaczyk, Head of the Molecular Mechanisms of Photosynthesis project group at RUB. When it comes to the so-called green gap in particular, PSII is almost inactive. "Cyanobacteria have solved the problem by forming special light-collecting proteins, i.e. phycobilisomes, which also make use of this light. This cooperation works in nature, but not yet in the test tube."In collaboration with the research group of Professor Wolfgang Schuhmann at RUB and the Israeli research group of Professor Noam Adir, Nowaczyk's team has succeeded in producing a two-component bioelectrode. The main difficulty was the functional interaction of the multiprotein complexes, some of which were combined across species.The researchers stabilised these super complexes using short-chain chemical crosslinkers that permanently fix the proteins at a very short distance from each other. In the next step, they inserted them into appropriate electrode structures. "We mastered this challenge by using customised, three-dimensional and transparent electrodes in combination with redox-active hydrogels," says Dr. Volker Hartmann, lead author of the study. This design enabled the researchers to use twice as many photons within the green gap, compared to a system without any light collection complexes.The assembly of protein complexes in the test tube is considered a promising interim stage in the development of biological solar cells. The advantages of different species can thus be functionally combined in semi-artificial systems. In future, the researchers will be mainly focusing on optimising the production and life span of the biological components.FundingThe research was funded by the Ruhr Explores Solvation Resolv Cluster of Excellence, the GRK 2341 Microbial Substrate Conversion Research School (Micon), which are financed by the German Research Foundation (DFG), and the German-Israeli research project Nano-engineered opto-bioelectronics with biomaterials and bio-inspired assemblies under the auspices of the DFG and the Israel Science Foundation.

Microbes

June 1, 2020

https://www.sciencedaily.com/releases/2020/06/200601113324.htm

Universal virus detection platform to expedite viral diagnosis

The prompt, precise, and massive detection of a virus is the key to combat infectious diseases such as Covid-19. A new viral diagnostic strategy using reactive polymer-grafted, double-stranded RNAs will serve as a pre-screening tester for a wide range of viruses with enhanced sensitivity.

Currently, the most widely using viral detection methodology is polymerase chain reaction (PCR) diagnosis, which amplifies and detects a piece of the viral genome. Prior knowledge of the relevant primer nucleic acids of the virus is quintessential for this test.The detection platform developed by KAIST researchers identifies viral activities without amplifying specific nucleic acid targets. The research team, co-led by Professor Sheng Li and Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering, constructed a universal virus detection platform by utilizing the distinct features of the PPFPA-grafted surface and double-stranded RNAs.The key principle of this platform is utilizing the distinct feature of reactive polymer-grafted surfaces, which serve as a versatile platform for the immobilization of functional molecules. These activated surfaces can be used in a wide range of applications including separation, delivery, and detection. As long double-stranded RNAs are common byproducts of viral transcription and replication, these PPFPA-grafted surfaces can detect the presence of different kinds of viruses without prior knowledge of their genomic sequences."We employed the PPFPA-grafted silicon surface to develop a universal virus detection platform by immobilizing antibodies that recognize double-stranded RNAs," said Professor Kim.To increase detection sensitivity, the research team devised two-step detection process analogues to sandwich enzyme-linked immunosorbent assay where the bound double-stranded RNAs are then visualized using fluorophore-tagged antibodies that also recognize the RNAs' double-stranded secondary structure.By utilizing the developed platform, long double-stranded RNAs can be detected and visualized from an RNA mixture as well as from total cell lysates, which contain a mixture of various abundant contaminants such as DNAs and proteins.The research team successfully detected elevated levels of hepatitis C and A viruses with this tool."This new technology allows us to take on virus detection from a new perspective. By targeting a common biomarker, viral double-stranded RNAs, we can develop a pre-screening platform that can quickly differentiate infected populations from non-infected ones," said Professor Li."This detection platform provides new perspectives for diagnosing infectious diseases. This will provide fast and accurate diagnoses for an infected population and prevent the influx of massive outbreaks," said Professor Kim.This work is featured in

Microbes

June 1, 2020

https://www.sciencedaily.com/releases/2020/06/200601113319.htm

Cancer cells cause inflammation to protect themselves from viruses

Researchers at the Francis Crick Institute have uncovered how cancer cells protect themselves from viruses that are harmful to tumours but not to healthy cells. These findings could lead to improved viral treatments for the disease.

In their study, published in These viruses are sometimes used as a treatment to destroy cancer cells and stimulate an immune response against the tumour. However, they only work in a minority of patients and the reasons whether they are effective or not are not yet fully understood.The team examined the environment surrounding a tumour and how cancer cells interact with their neighbours, in particular, cancer-associated fibroblasts (CAFs), which researchers know play a significant role in cancer protection, growth and spread.They found that when cancer cells are in direct contact with CAFs, this leads to inflammation that can alert the surrounding tissue, making it harder for viruses to invade and replicate within the cancer cell.This protective inflammatory response occurs when cancer cells pass small amounts of cytoplasm, the fluid in their cells, through to the CAFs. This triggers the fibroblasts to signal to nearby cells to release cytokines, molecules that cause inflammation.*Erik Sahai, paper author and group leader of the Tumour Cell Biology Laboratory at the Crick says: "This process only occurs when cancer cells and fibroblasts are in direct contact with each other. In healthy tissue, this type of inflammatory response would only happen during injury, as there is usually a membrane keeping them apart."This is an excellent example of the way cancer hijacks our body's protective mechanisms for its own gain."Importantly, when the researchers blocked the signalling pathway in cell cultures and in tumours grown in the laboratory, they found that the cancer cells became more sensitive to oncolytic viruses.They hope these findings may, in the future, help to develop a treatment that could modulate the inflammation and so help oncolytic viruses to more effectively target cancer cells.Emma Milford, co-lead author and Phd student in the Tumour Cell Biology Laboratory at the Crick says: "If we can more fully understand how cancer cells protect themselves from oncolytic viruses and find effective ways to stop these protective mechanisms, these viruses could become a more powerful tool doctors can use to treat cancer. This research is an important, early step towards this."Antonio Rullan, co-lead author and clinical research fellow in the Tumour Cell Biology Laboratory at the Crick adds: "These viruses prefer to target cancer cells over healthy cells, which has made them of interest for scientists over the last few decades. However, much more remains to be understood about how they interact with tumours and the immune system."The researchers plan to continue this work and study exactly how the cytoplasm is transferred from one cell to another.

Microbes

May 29, 2020

https://www.sciencedaily.com/releases/2020/05/200529150640.htm

The most common organism in the oceans harbors a virus in its DNA

The most common organism in the oceans, and possibly on the entire planet, is a family of single-celled marine bacteria called SAR11. These drifting organisms look like tiny jelly beans and have evolved to outcompete other bacteria for scarce resources in the oceans.

We now know that this group of organisms thrives despite -- or perhaps because of -- the ability to host viruses in their DNA. A study published in May in University of Washington oceanographers discovered that the bacteria that dominate seawater, known as Pelagibacter or SAR11, hosts a unique virus. The virus is of a type that spends most of its time dormant in the host's DNA but occasionally erupts to infect other cells, potentially carrying some of its host's genetic material along with it."Many bacteria have viruses that exist in their genomes. But people had not found them in the ocean's most abundant organisms," said co-lead author Robert Morris, a UW associate professor of oceanography. "We suspect it's probably common, or more common than we thought -- we just had never seen it."This virus' two-pronged survival strategy differs from similar ones found in other organisms. The virus lurks in the host's DNA and gets copied as cells divide, but for reasons still poorly understood, it also replicates and is released from other cells.The new study shows that as many as 3% of the SAR11 cells can have the virus multiply and split, or lyse, the cell -- a much higher percentage than for most viruses that inhabit a host's genome. This produces a large number of free viruses and could be key to its survival."There are 10 times more viruses in the ocean than there are bacteria," Morris said. "Understanding how those large numbers are maintained is important. How does a virus survive? If you kill your host, how do you find another host before you degrade?"The study could prompt basic research that could help clarify host-virus interactions in other settings."If you study a system in bacteria, that is easier to manipulate, then you can sort out the basic mechanisms," Morris said. "It's not too much of a stretch to say it could eventually help in biomedical applications."The UW oceanography group had published a previous paper in 2019 looking at how marine phytoplankton, including SAR11, use sulfur. That allowed the researchers to cultivate two new strains of the ocean-dwelling organism and analyze one strain, NP1, with the latest genetic techniques.Co-lead author Kelsy Cain collected samples off the coast of Oregon during a July 2017 research cruise. She diluted the seawater several times and then used a sulfur-containing substance to grow the samples in the lab -- a difficult process, for organisms that prefer to exist in seawater.The team then sequenced this strain's DNA at the UW PacBio sequencing center in Seattle."In the past we got a full genome, first try," Morris said. "This one didn't do that, and it was confusing because it's a very small genome."The researchers found that a virus was complicating the task of sequencing the genome. Then they discovered a virus wasn't just in that single strain."When we went to grow the NP2 control culture, lo and behold, there was another virus. It was surprising how you couldn't get away from a virus," said Cain, who graduated in 2019 with a UW bachelor's in oceanography and now works in a UW research lab.Cain's experiments showed that the virus' switch to replicating and bursting cells is more active when the cells are deprived of nutrients, lysing up to 30% of the host cells. The authors believe that bacterial genes that hitch a ride with the viruses could help other SAR11 maintain their competitive advantage in nutrient-poor conditions."We want to understand how that has contributed to the evolution and ecology of life in the oceans," Morris said.

Microbes

May 28, 2020

https://www.sciencedaily.com/releases/2020/05/200528172002.htm

How bacteria purge toxic metals

Bacteria have a cunning ability to survive in unfriendly environments.

For example, through a complicated series of interactions, they can identify -- and then build resistance to -- toxic chemicals and metals, such as silver and copper. Bacteria rely on a similar mechanism for defending against antibiotics.In Cornell researchers combined genetic engineering, single-molecule tracking and protein quantitation to get a closer look at this mechanism and understand how it functions. The knowledge could lead to the development of more effective antibacterial treatments.The team's paper, "Metal-Induced Sensor Mobilization Turns on Affinity to Activate Regulator for Metal Detoxification in Live Bacteria," published May 28 in "We were really interested in the fundamental mechanism," said Peng Chen, the Peter J.W. Debye Professor of Chemistry in the College of Arts and Sciences and the paper's senior author. "The broader concept is that once we know the mechanism, then perhaps we can come up with better or alternative ways to compromise bacteria's ability in defending against toxic chemicals. That will hopefully contribute to designing new ways of taming bacterial drug resistance."The bacteria's resistance is actually a tag-team operation, with two proteins working together inside the cell. One protein (CusS), in the inner membrane, senses the presence of the chemical or metal and sends a signal to a regulator protein (CusR) in the cytosol, or intercellular fluid. The regulator protein binds to DNA and activates a gene that generates transport proteins, which purge the toxin from the cell.Typically, scientists analyze these functions by using biochemical assays that remove the protein from the cell. However, that process prevents the scientists from observing the proteins in their native environment, and certain details, such as the spatial arrangement between proteins, have remained murky.For a deeper analysis, Chen's team used single-cell imaging, whereby they tagged individual proteins in living The team was specifically interested in the activities of sensor proteins, which come in two varieties -- those that cluster together and those that move around the inner membrane. The researchers found that when "One of the unknowns among the steps is at what point the sensor protein forms a protein-protein complex with the regulator protein," Chen said. "We found that as soon as the sensor binds copper, it already causes its recruitment of this regulator protein. This occurs really, really early in this sequence of events."The early recruitment provides a functional advantage by initiating the sequence and quickly speeding it along before the sequence has time to decay. Chen likens this strategy to a game of hot potato."If I hold a hot potato and want to give it to you, I don't want to hold the potato before calling you over," Chen said. "I want you to be right next to me, so I can immediately pass it to you. Otherwise, the hot potato becomes cold. Or it's too hot, so I have to throw it away. In chemical terms, basically that species would decay or transfer to something else."

Microbes

May 28, 2020

https://www.sciencedaily.com/releases/2020/05/200528115806.htm

Exploiting viruses to attack cancer cells

An adenovirus is now better able to target and kill cancer cells due to the addition of an RNA stabilizing element.

Hokkaido University scientists have made an adenovirus that specifically replicates inside and kills cancer cells by employing special RNA-stabilizing elements. The details of the research were published in the journal Much research in recent years has investigated genetically modifying adenoviruses to kill cancers, with some currently being tested in clinical trials. When injected, these adenoviruses replicate inside cancer cells and kill them. Scientists are trying to design more efficient viruses, which are better able to target cancer cells while leaving normal cells alone.Hokkaido University molecular oncologist Fumihiro Higashino led a team of scientists to make two new adenoviruses that specifically target cancer cells. To do this, they used 'adenylate-uridylate-rich elements' (AREs), which are signals in RNA molecules known to enhance the rapid decay of messenger RNAs (mRNAs) in human cells. "AREs make sure that mRNAs don't continue to code for proteins unnecessarily in cells," explains Higashino. "Genes required for cell growth and proliferation tend to have AREs."Under certain stress conditions, however, ARE-containing mRNAs can become temporarily stabilized allowing the maintenance of some necessary cell processes. ARE-mRNAs are also stabilized in cancer cells, supporting their continuous proliferation.Higashino and his team inserted AREs from two human genes into an adenovirus replicating gene, making the new adenoviruses: AdARET and AdAREF. "The idea behind the insertion is that the AREs will stabilize the killer adenoviruses, allowing them to replicate only inside cancer cells but not in normal healthy ones," says Higashino.Indeed, AdARET and AdAREF were both found to replicate inside and kill cancer cells in the laboratory, while they hardly affected normal cells. Tests confirmed that the specific replication in cancer cells was due to stabilization of the viral genes with AREs, which did not happen in the healthy cells.The scientists then injected human cancer cells under the skin of nude mice, which then developed into tumors. When AdARET and AdAREF were injected into the tumors, they resulted in a significant reduction in tumor size.This wasn't the first time for the team to test the use of AREs in adenoviruses. In a previous study, another scientist used an ARE belonging to a different gene and found this adenovirus worked specifically in cancers containing a mutation in a gene called RAS. AdARET and AdAREF, on the other hand, were found to be effective against cancer cells without a mutated RAS gene, making the viruses applicable to a wider range of cancer cells."Since ARE-mRNA stability has also been reported in diseases other than cancer, we think the viruses we engineered could also have potential for treating diseases related to inflammations, viral infection, hypoxia, and ultraviolet irradiation," says Higashino.

Microbes

May 27, 2020

https://www.sciencedaily.com/releases/2020/05/200527105055.htm

Superworms digest plastic, with help from their bacterial sidekicks

Resembling giant mealworms, superworms (

Polystyrene is used in packaging containers, disposable cups and insulating materials. When thrown in landfills or littered in the environment, the plastic takes several hundred years to completely break down. Recently, several studies have found that mealworms and superworms can ingest and degrade polystyrene within a few weeks. In mealworms, this ability was linked to a certain strain of polystyrene-degrading bacteria in the worms' gut. Jiaojie Li, Dae-Hwan Kim and colleagues wanted to search for similar bacteria in superworms.The team placed 50 superworms in a chamber with polystyrene as their only carbon source, and after 21 days, the worms had consumed about 70% of the plastic. The researchers then isolated a strain of

Microbes

May 27, 2020

https://www.sciencedaily.com/releases/2020/05/200526173818.htm

Exposure to 'good bacteria' during pregnancy buffers risk of autism-like syndrome

Giving beneficial bacteria to stressed mothers during the equivalent of the third trimester of pregnancy prevents an autism-like disorder in their offspring, according to a new animal study by University of Colorado Boulder researchers.

The study, published in the journal It's among the first studies to suggest that such exposures during pregnancy influence neurodevelopment of a fetus and, while far more research is necessary, could open the door to new prenatal interventions."It suggests that you could develop microbial interventions that lower the risk of neurodevelopmental syndromes like autism," said co-author Christopher Lowry, an associate professor in the Department of Integrative Physiology.In humans, research has long shown that maternal stress during pregnancy prompts systemic inflammation in both the mother and fetus and is a risk factor for autism, said senior author Daniel Barth, a professor of psychology and neuroscience.In a previous study, Barth found that when rats were stressed and given a drug called terbutaline, which is often administered to women to delay preterm labor, their offspring demonstrated an autism-like syndrome -- including the two hallmark features of social deficits and repetitive behavior. They also developed an epilepsy-like seizure disorder."Our fundamental question with this new study was whether we could use an immunoregulatory microbe to prevent the long-term consequences of environmental stressors during pregnancy," said first author Zachariah Smith, a post-doctoral researcher in Barth's lab.For the study, the researchers exposed rats to mild stressors and gave them terbutaline during what would be the equivalent of the third trimester of pregnancy in humans.Half were also given a series of injections of a heat-killed preparation of a friendly bacterium known as At two and four months, the pups were given a series of tests assessing, among other things, their degree of social interaction and whether they exhibited repetitive behaviors.As in the previous study, those whose mothers had been stressed and given terbutaline showed autism-like behaviors. But those who had been immunized with "Immunization with The inoculation did not appear to protect against development of seizure disorders. But because epilepsy tends to develop later in life, the researchers intend to repeat the experiment with a larger sample size and longer treatment period.Autism and epilepsy often manifest together in humans, with about 30% of autistic individuals exhibiting epileptic symptoms, such as seizures. Stress-induced inflammation likely plays a role in both, the researchers suspect."It could be that if we continue the treatment for longer we could also prevent the development of some cases of epilepsy, but much more research is necessary," said Lowry.The researchers caution that they are not developing an "autism vaccine" and they are not suggesting that microbial interventions could reverse the disorder in children who already have it. But their study does reinforce the idea that exposure to beneficial microorganisms, sometimes referred to as "old friends," can play a critical role in brain development in utero.Ultimately, Lowry envisions a day when stressed moms deemed particularly high risk of having a child with a neurodevelopmental disorder could be given a specially formulated probiotic or inoculation to support healthy brain development of their child."This is the first maternal intervention that I know of that has been able to prevent an autism-like syndrome, including the behavioral and social aspects," Lowry said. "If this could be replicated in humans, that would be pretty profound."Meantime, they say, mothers should be cognizant of the potential risks of emotional and environmental stressors, including the drug terbutaline, during pregnancy.And they should try to expose themselves to beneficial bacteria, through fermented foods like yogurt and sauerkraut and even time spent in nature.

Microbes

May 29, 2020

https://www.sciencedaily.com/releases/2020/05/200529161301.htm

Key player in hepatitis A virus infection

How hepatitis A virus (HAV) manages to enter liver cells called hepatocytes and initiate infection had remained a mystery for fifty years until now. University of North Carolina School of Medicine researchers designed experiments using gene-editing tools to discover how molecules called gangliosides serve as de facto gatekeepers to allow the virus entry into liver cells.

The research, published in "Discovering that gangliosides are essential receptors for HAV infection adds an interesting plot twist to the hepatitis A story," said senior author Stanley Lemon, MD, professor of medicine and microbiology at the UNC School of Medicine and member of the UNC Institute for Global Health and Infectious Diseases. "Gangliosides are structurally similar across mammalian species, unlike proteins, which helps explain cross-species transmission of ancient hepatoviruses. Understanding what helps a virus jump from one animal species to another is incredibly important, as evidenced so plainly by the current Covid-19 pandemic."HAV was discovered nearly 50 years ago, and although there is a vaccine, there is no treatment. The virus still infects more than 1.4 million people globally each year, and in recent years has been causing increasing numbers of hepatitis cases in the United States, some fatal. Many people experience very mild or no symptoms, especially children. Patients with symptoms, which can last eight weeks and sometimes longer, often experience nausea, vomiting, diarrhea, jaundice, fever, and abdominal pain. After initial infection, 10 to 15 percent of infected individuals experience a recurrence of symptoms during the first six months. Acute liver failure is rare, but more common in elderly people.HAV infects people through mechanisms similar to other viruses; it interacts with receptor molecules on the surface of human cells to gain entry. Knowing the receptor for a virus not only helps researchers understand how the virus enters cells, but also creates opportunities to design antivirals to block the interaction to prevent or treat disease.Among the five known hepatitis viruses that cause acute or chronic liver disease in humans, receptors have been identified for hepatitis C virus and hepatitis B virus. For hepatitis A, the identity of the receptor remained elusive. The black sheep of the picornavirus family, it uniquely exists in two modes: as nonenveloped (naked) viruses (nHAV), comprised of a protein shell called a capsid surrounding an RNA genome; or as 'quasi-enveloped' viruses (eHAV), in which capsids containing the viral genome are cloaked inside host cell membranes.Once inside the liver, eHAV is released from infected hepatocytes to circulate in the blood, whereas naked nHAV particles are shed in feces. Both virus types are infectious. Being cloaked with host-derived membranes gives eHAV an advantage in evading antibody responses, while the naked virion is extraordinarily stable and spreads readily in the environment. But how did each virus get into liver cells and the blood in the first place?Years ago, the human protein TIM1 was reported to be a receptor for HAV. The gene that encodes this protein even bears the official name HAV cellular receptor 1 (HAVCR1). But recent studies in Lemon's laboratory showed that cells lacking TIM1 still allow HAV infection.To find a more likely culprit for the receptor, Anshuman Das, PhD, a postdoc in the Lemon lab at the time of this research and now at Duke University., used CRISPR-Cas9 gene editing to knock out approximately 20,000 genes in cultured cells to find which human genes are essential for the virus to invade. They identified five particular genes, all of which were required by the virus. Turns out, these genes encode enzymes or transporters that make possible the synthesis of gangliosides. (Transporters are molecules that traffic chemicals across channels inside cells.)Gangliosides are sugary fatty acid molecules. The enzyme ceramide glucosyltransferase creates gangliosides. And the gene UGCG encodes for that enzyme."UGCG was the lead culprit of the five genes that lit up our screen using CRISPR-Cas9," Lemon said.The researchers then knocked out UGCG, which prevented HAV infection. They also treated liver-derived cells with a chemical inhibitor of ceramide glucosyltransferase to prevent both eHAV and nHAV infection.The researchers then injected synthetic HAV RNA directly into cells to discover that the viral RNA replicated well, suggesting that gangliosides were required for entry of the virus into cells, but not needed for it to make copies of its genome, or new virus particles, once it gets into cells.Subsequent experiments revealed that -- in the absence of gangliosides -- both naked and quasi-enveloped HAV particles do in fact get part way into the cell, but they end up getting stuck in a compartment called the lysosome. Viral replication does not occur. When the researchers added back gangliosides, the accumulated viruses used the gangliosides to exit the lysosome and continue their invasion of the cell, ending up releasing their genomes into the cell cytoplasm where the virus then began to replicate."This means gangliosides are essential for a late-step entry of HAV into cells," said Anshuman Das, PhD, a postdoc in the Lemon lab at the time of this research and now at Duke University. "They function as true receptors."Although questions remain, the researchers say that understanding the role of gangliosides may open up new avenues for prevention and possibly even treatment of hepatitis A.

Microbes

May 26, 2020

https://www.sciencedaily.com/releases/2020/05/200526145251.htm

Terrestrial bacteria can grow on nutrients from space

Interest in space exploration is increasing again. In the past decade, there has been renewed thinking about missions to the moon, perhaps even to Mars. As inevitable fellow travellers on the bodies of astronauts, spaceships, or equipment, terrestrial microorganisms will undoubtedly come into contact with extraterrestrial environments. Researchers from the Radboudumc describe in an article in

No matter how well astronauts and material are decontaminated, co-travelling microorganisms into space cannot be prevented. Given the enormous adaptability potential of bacteria, it is conceivable that they will sometimes survive space travel and be able to settle in an extraterrestrial environment.For this study, four non-fastidious environment-derived bacterial species with pathogenic features were selected, including Klebsiella pneumoniae and Pseudomonas aeruginosa. A minimal 'diet' based on nitrogen, phosphorus, sulphur, iron and water to which carbohydrates found in carbonaceous meteorites were added was made to determine whether extraterrestrial survival and growth were possible. The four bacterial species were shown to survive and multiply on this minimal 'diet'.In follow-up experiments, the team of researchers observed that the adaptation of bacteria, especially in the case of K. pneumoniae, caused changes in the cell membrane -- the shell of the cell -- as a result of which the immune system reacted more strongly to the bacteria. In short, the bacteria become more immunogenic. Research in cell culture, but also in mice, showed that the bacteria survive on extraterrestrial nutrients and become less virulent as a result of this necessary adaptation. At the same time, this research shows that bacteria can survive under these conditions, which means that the risk of infection among space travellers remains, precisely because -- as other researchers have shown -- a space journey has negative effects on the functioning of the immune system, making astronauts more susceptible to infections.

Microbes

May 26, 2020

https://www.sciencedaily.com/releases/2020/05/200526134655.htm

Biotechnology: Metal collector made of bacteria

Bacteria, fungi and plants sometimes produce metal-binding substances that can be harnessed, for example for the extraction of raw materials, for their separation, for cleaning soils or for medical purposes. Researchers now outline how these natural substances or modified semi-artificial variants of them can be produced according to genetic information.

Microorganisms such as fungi and bacteria as well as plants generate a wide range of chemical substances that are not absolutely necessary for their survival. Such so-called secondary metabolites are usually formed in response to current environmental conditions. They include metal-binding molecules called chelators. The best described group of chelators are the iron-binding siderophores. They are relevant for many metabolic processes, as iron is an essential component of many enzymes and signalling pathways. For example, pathogenic bacteria use siderophores to extract iron from their host for their metabolism. The host might then suffer from iron deficiency. But siderophores are also used by bacteria living in soil that thus get access to iron and, as a result, gain an advantage over other organisms in the same habitat. In addition to iron-specific chelators, there are a number of others for various metals and metalloids such as zinc, vanadium, molybdenum or even uranium oxides."Such chelators have many potential applications," explains Dirk Tischler. "They can be used, for example, to remediate floors, selectively extract or separate raw materials, or in biosensorics or medicine." In medical applications, siderophores are used to treat iron overload in the body, a disorder known as "iron storage disease."Over the last few years, his research group, together with other teams, has identified further strains that form chelators and described new structures. They have also successfully deciphered the genetic information for the formation of these substances and introduced them into easy-to-handle organisms such as Escherichia coli bacteria. These bacteria then serve as producers of the required natural substances or of modified substances. "This is how we can create semi-artificial compounds," says Dirk Tischler.In the review article, he describes the different natural chelators and their ability to bind metals and metalloids and explores current and potential future applications. "At present, we are using the knowledge we've gained so far to create artificial biosynthetic pathways that enable us to generate and characterise precursors of siderophores," concludes Tischler. These precursors will subsequently be chemically modified in order to gain access to new drug classes.The research was partially funded by Dechema within the framework of the Max Buchner scholarship MBFSt 3646 and the Ministry of Innovation, Science and Research in North Rhine-Westphalia (PtJ-TRI/1141ng006).

Microbes

May 26, 2020

https://www.sciencedaily.com/releases/2020/05/200526124040.htm

How maternal intestinal microbiota is involved in fetal development

All mammals, including humans, are colonized by billions of microbes. These mainly live in our intestines but can also be found in the respiratory tract, on the skin and in the urogenital tract. In the gastroenterology research group of the Department for BioMedical Reserarch (DBMR) at the University of Bern and at the University Hospital Bern, Inselspital, Stephanie Ganal-Vonarburg and Andrew Macpherson investigate the interaction of these benign intestinal microbes with the host organism.

The positive influence of the intestinal flora on our immune system has been recognized for a long time. Interestingly, even the maternal intestinal microbiota already has an effect on the development of the child's immune system during pregnancy as well as immediately after birth. In a review article published in the journal Scientists have always assumed that the developing embryo and fetus grow in a completely sterile environment in the womb, i.e. in the absence of colonizing microbes, and that colonization with microbes only takes place at the time of birth. "However, the fetus is not protected against microbial metabolites that originate from the maternal intestinal flora," says Ganal-Vonarburg. The placenta offers only partial protection and transfer of microbial substances leads to the maturation of the offspring innate immune system already during pregnancy. Previous studies by the group around Ganal-Vonarburg and Macpherson have shown this."It is common for pregnant women to take medication with great caution and only after consulting their doctor, since many medications can cross the placenta and interfere with the child's development. However, much less is known about which naturally occurring substances present in the diet can pass on to the unborn child and to what extent this can be beneficial or harmful for the development of the child's immune system," explains Ganal-Vonarburg.Together with Andrew Macpherson, she has now summarized published research results and found evidence that metabolic products from the diet cannot only directly reach the maternal organism and thus into the developing fetus, but that this often only occurs after metabolism through the intestinal flora. This also applies to the intake of herbal products, such as superfoods that are considered particularly healthy during pregnancy, such as goji berries or chia seeds: "Although plants products are 'natural' substances, they are always so-called xenobiotic substances that are foreign to the body and should be handled very carefully," says Macpherson. "Especially when pregnant women take plant-based products in large quantities."Ganal-Vonarburg and Macpherson recommend that future studies should investigate which natural substances could have a beneficial or negative effect on the development of the unborn child and what influence differences in the maternal intestinal flora can have on this process.

Microbes

May 26, 2020

https://www.sciencedaily.com/releases/2020/05/200526091359.htm

Ocean virus hijacks carbon-storing bacteria

Beneath the ocean's surface, a virus is hijacking the metabolism of the most abundant organism on Earth. That may be of interest to those of us above who breathe.

Rice University scientists analyzed the role of ferredoxin proteins produced when phages alter the ability of But phages are not their friends. The virus strengthens itself by stealing energy the bacteria produces from light, reprogramming its victim's genome to alter how it transfers electrons."The growth in the range of this organism in the oceans could increase the total carbon stored by these microbes," he said. "Alternatively, the viruses that infect these bacteria could alter carbon fixation and potentially prevent gigatons of carbon from being taken out of the air annually, according to one recent projection."Campbell said the goal of the study was to explore the variety of ways viruses interact with their hosts. In the process, the researchers discovered the phage wrests control of electron flow in the host itself, rewiring the bacteria's metabolism. "When the virus infects, it shuts down production of the bacterial proteins and replaces it with its own variants," he said. "I compare it to putting a different operating system in a computer."The researchers used synthetic biology techniques to mix and match phage and cyanobacterial proteins to study how they interact. A part of the study led by Rice biochemist George Phillips also determined for the first time the structure of a key cyanophage ferredoxin protein."A phage would usually go into a cell and kill everything," said Rice synthetic biologist Jonathan Silberg, the study's lead scientist and director of the university's Systems, Synthetic and Physical Biology program."But Ian's results suggest these phages are establishing a complex control mechanism," he said. "I wouldn't say they've zombified their hosts, because they allow the cells to continue doing some of their own housekeeping. But they're also plugging in their own ferredoxins, like power cables, to fine tune the electron flow."Instead of working directly with cyanophages and "Taking a phage and a cyanobacteria from the ocean and trying to study the biology, especially electron flow, would be really hard to do through classical biochemistry," Silberg said. "Ian literally took partners from both the phage and the host, put them together by encoding their DNA in another cellular system, and was able to quickly develop some interesting results."It's an interesting application of synthetic biology to understand complex things that would otherwise be arduous to measure," he said.The researchers suspect the protein they modeled in

Microbes

May 26, 2020

https://www.sciencedaily.com/releases/2020/05/200526111306.htm

Microbial cyborgs: Bacteria supplying power

Electronic devices are still made of lifeless materials. One day, however, "microbial cyborgs" might be used in fuel cells, biosensors, or bioreactors. Scientists of Karlsruhe Institute of Technology (KIT) have created the necessary prerequisite by developing a programmable, biohybrid system consisting of a nanocomposite and the

The bacterium The team of Professor Christof M. Niemeyer has now succeeded in developing a nanocomposite that supports the growth of exoelectrogenic bacteria and, at the same time, conducts current in a controlled way. "We produced a porous hydrogel that consists of carbon nanotubes and silica nanoparticles interwoven by DNA strands," Niemeyer says. Then, the group added the bacterium Such a system does not only have to be conductive, it also must be able to control the process. This was achieved in the experiment: To switch off the current, the researchers added an enzyme that cuts the DNA strands, as a result of which the composite is decomposed."As far as we know, such a complex, functional biohybrid material has now been described for the first time. Altogether, our results suggest that potential applications of such materials might even extend beyond microbial biosensors, bioreactors, and fuel cell systems," Niemeyer emphasizes.

Microbes

May 25, 2020

https://www.sciencedaily.com/releases/2020/05/200525115646.htm

Scientists find genes to save ash trees from deadly beetle

An international team of scientists have identified candidate resistance genes that could protect ash trees from the Emerald Ash Borer (EAB), a deadly pest that is expected to kill billions of trees worldwide.

In the new study, published today in Meanwhile, collaborators from the United States Department of Agriculture Forest Service in Ohio tested resistance of over 20 ash tree species to EAB by hatching eggs attached to the bark of trees, and following the fate of the beetle larvae. Resistant ash trees generally killed the larvae when they burrowed into their stems, but susceptible ones did not.The research team observed that several of the resistant species were more closely related to susceptible species than to other resistant species. This meant the UK-based genome scientists were able to find resistance genes, by looking for places within the DNA where the resistant species were similar, but showed differences from their susceptible relatives.Using this novel approach, the scientists revealed 53 candidate resistance genes, several of which are involved in making chemicals that are likely to be harmful to insects.The findings suggest that breeding or gene editing could be used to place these resistance genes into ash species currently affected by EAB.EAB has killed hundreds of millions of ash trees in North America over the last 10 years. Whilst individual ash trees can be protected by using insecticides, the only long-term solution for saving American ash populations is to breed trees with resistance to EAB.The beetle is also a threat to European ash populations. It was discovered near Moscow around 15 years ago and has now spread into Ukraine.In the study, the US researchers found that European ash was more resistant to EAB than the North American species. However, European ash trees are already affected by an epidemic of the fungal disease, ash dieback, and experts are yet to understand how the two threats might interact.The study also involved colleagues from the United States Department of Agriculture's Agricultural Research Service and the Teagasc Forestry Development Department, Dublin, Republic of Ireland.Dr Laura Kelly, an academic visitor at Queen Mary, Research Leader in Plant Health at the Royal Botanic Gardens, Kew and first author of the study, said: "Ash trees are key components of temperate forest ecosystems and the damage caused by EAB also puts at risk the many benefits that these forests provide. Our findings suggest that it may be possible to increase resistance in susceptible species of ash via hybrid breeding with their resistant relatives or through gene editing. Knowledge of genes involved in resistance will also help efforts to identify trees that are able to survive the ongoing threat from EAB, and in turn, could facilitate restoration of ash woodlands in areas which have already been invaded."Professor Richard Buggs, Professor of Evolutionary Genomics at Queen Mary and Senior Research Leader in Plant Health at the Royal Botanic Gardens, Kew, said: "The emerald ash borer has killed hundreds of millions of ash trees in North America since it was accidentally imported to Detroit from Asia in wooden packaging. The beetle is now spreading across Europe, where we don't yet know how it will interact with the invasive fungal pathogen causing the ash dieback epidemic. We need to be prepared to take decisive action to stop the spread of pests and pathogens that damage trees and the natural environment, as well as pathogens that attack humans."Dr Jennifer Koch, Research Biologist with the United States Department of Agriculture Forest Service, said: "These candidate resistance genes, once validated, have the potential to greatly expedite the breeding process and the production of improved planting stock for restoration of forests and landscapes decimated by EAB."Professor Melanie Welham, BBSRC's Executive Chair, said: "These significant research findings demonstrate the importance of international collaboration to further fundamental knowledge of pathogen biology. By having a better understanding of the implications of tree diseases globally we are able to ensure appropriate approaches to their management."

Microbes

May 22, 2020

https://www.sciencedaily.com/releases/2020/05/200522095506.htm

New technology can detect anti-virus antibody in 20 minutes

Researchers have succeeded in detecting anti-avian influenza virus antibody in blood serum within 20 minutes, using a portable analyzer they have developed to conduct rapid on-site bio tests. If a suitable reagent is developed, this technology could be used to detect antibodies against SARS-CoV-2, the causative virus of COVID-19.

Avian influenza is a poultry disease caused by influenza A virus infection. Rapid initial response for a suspected infection and continuous surveillance are essential to mitigate the damage from highly pathogenic, transmittable pathogens such as avian influenza viruses.Generally, the polymerase chain reaction (PCR) method is used to detect the viral genome, but its complicated procedure requires a considerable amount of time. Another method involves detecting antibodies produced in the body in reaction to virus infection. However, widely used antibody detection methods can be inaccurate because the antibodies' existence is generally determined by eyesight.The group, including Keine Nishiyama, a doctoral student at Hokkaido University's Graduate School of Chemical Science and Engineering, and Professor Manabu Tokeshi of the university's Faculty of Engineering, conducted this study to develop a new method and analyzer capable of rapid, facile and selective detection of antibodies. The method is based on conventional fluorescence polarization immunoassay (FPIA) but applies a different measurement mechanism to make the analyzer much smaller and portable. The analyzer weighs only 5.5 kilograms.The combined use of liquid crystal molecules, an image sensor and the microfluidic device makes it possible to simultaneously examine multiple samples and reduces the volume of each sample required. Liquid crystal molecules are capable of controlling the polarization direction of fluorescent light, while the microfluidic device has a number of microchannels as a measurement vessel.The group also developed a reagent to detect anti-H5 avian influenza virus antibody, a fluorescein-labeled protein that binds only with the antibody. The reagent was made by reproducing hemagglutinin (HA) protein fragments, which are expressed on the surface of H5 avian influenza virus, through gene recombination and by labeling fluorescent molecules to the fragments.To make the measurement, serum collected from birds was mixed with the reagent and left for 15 minutes. The mixture was injected into the microfluidic device and measured with the portable fluorescence polarization analyzer. Molecular movements of the reagent bound with the antibody will be smaller in the liquid, producing a different degree of polarization from the reagent not bound with the antibody. The system can detect anti-H5 avian influenza virus antibody with only 2 microliters of serum sample and within 20 minutes."Our analyzer could be used to conduct other bio tests if suitable reagents are developed," says Tokeshi. The group has already successfully detected mycotoxin and drug constituents. "By reproducing fragments of spike proteins expressed in the novel coronavirus, and using them as the reagent, the analyzer should be able to detect anti-coronavirus antibodies."

Microbes

May 20, 2020

https://www.sciencedaily.com/releases/2020/05/200520131701.htm

Elucidating the mechanism of a light-driven sodium pump

Researchers at the Paul Scherrer Institute PSI have succeeded for the first time in recording, in action, a light-driven sodium pump from bacterial cells. The findings promise progress in the development of new methods in neurobiology. The researchers used the new X-ray free-electron laser SwissFEL for their investigations. They have published their findings today in the journal

Sodium, which is contained in ordinary table salt, plays an essential role in the vital processes of most biological cells. Many cells build up a concentration gradient between their interior and the environment. For this purpose, special pumps in the cell membrane transport sodium out of the cell. With the help of such a concentration gradient, cells of the small intestine or the kidneys, for example, absorb certain sugars.Such sodium pumps are also found in the membranes of bacteria. They belong to the family of the so-called rhodopsins. These are special proteins that are activated by light. For example, rhodopsins transport sodium out of the cell in the case of bacteria living in the ocean, such as Krokinobacter eikastus. The crucial component of rhodopsin is the so-called retinal, a form of vitamin A. It is of central importance for humans, animals, certain algae and many bacteria. In the retina of the human eye, for example, retinal initiates the visual process when it changes shape under the influence of light.Researchers at the Paul Scherrer Institute PSI have now succeeded capturing images of the sodium pump of Krokinobacter eikastus in action and documenting the molecular changes necessary for sodium transport. To do this, they used a technique called serial femtosecond crystallography. A femtosecond is one-quadrillionth of a second; a millisecond is the thousandth part. The sample to be examined -- in this case a crystallised sodium pump -- is struck first by a laser and then by an X-ray beam. In the case of bacterial rhodopsin, the laser activates the retinal, and the subsequent X-ray beam provides data on structural changes within the entire protein molecule. Since SwissFEL produces 100 of these femtosecond X-ray pulses per second, recordings can be made with high temporal resolution. "We can only achieve temporal resolution in the femtosecond range at PSI with the help of SwissFEL," says Christopher Milne, who helped to develop the Alvra experimental station where the recordings were made. "One of the challenges is to inject the crystals into the setup so that they meet the pulses of the laser and the X-ray beam with pinpoint accuracy."In the current experiment, the time intervals between the laser and X-ray pulses were between 800 femtoseconds and 20 milliseconds. Each X-ray pulse creates a single image of a protein crystal. And just as a cinema film ultimately consists of a large number of individual photographs that are strung together in a series and played back rapidly, the individual pictures obtained with the help of SwissFEL can be put together to form a kind of film."The process that we were able to observe in our experiment, and which roughly corresponds to the transport of a sodium ion through a cell membrane, takes a total of 20 milliseconds," explains Jörg Standfuss, who heads the group for time-resolved crystallography in the Biology and Chemistry Division at PSI . "Besides elucidating the transport process, we were also able to show how the sodium pump achieves its specificity for sodium through small changes in its structure." This ensures that only sodium ions, and no other positively charged ions, are transported. With these investigations, the researchers also revealed the molecular changes through which the pump prevents sodium ions that have been transported out of the cell from flowing back into it.Since sodium concentration differences also play a special role in the way nerve cells conduct stimuli, neurons have powerful sodium pumps in their membranes. If more sodium flows into the cell's interior, a stimulus is transmitted. These pumps then transport the excess sodium in the cell to the outside again.Since the sodium pump of Krokinobacter eikastus is driven by light, researchers can now use it for so-called optogenetics. With this technology, cells, in this case nerve cells, are genetically modified in such a way that they can be controlled by light. The pump is installed in nerve cells using methods of molecular genetics. If it is then activated by light, a neuron can no longer transmit stimuli, for example, since this would require an increase in the sodium concentration in the nerve cell. However, bacterial rhodopsin prevents this by continuously transporting sodium out of the cell. Thus active sodium pumps render a neuron inactive."If we understand exactly what is going on in the sodium pump of the bacterium, it can help to improve experiments in optogenetics," says Petr Skopintsev, a PhD candidate in the time-resolved crystallography group. "For example, it can be used to identify variants of bacterial rhodopsin that work more effectively than the form that is usually found in Krokinobacter." In addition, the researchers hope to gain insights into how individual mutations can change the ion pumps so that they then transport ions other than sodium.

Microbes

May 20, 2020

https://www.sciencedaily.com/releases/2020/05/200520124928.htm

Uncovering the Achilles heel of viruses

A new research study headed by the Department of Biomedicine at Aarhus University, Denmark, identifies how viruses avoid the body's immune system and cause infections and diseases. The new knowledge could pave the way for the treatment of viral diseases such as COVID-19.

Viruses have an exceptional ability to circumvent the body's immune system and cause diseases. The majority of people recover from a viral infection such as influenza, although the current COVID-19 pandemic demonstrates how dangerous viruses are when there is no effective vaccine or treatment.Professor and virologist Søren Riis Paludan from the Department of Biomedicine at Aarhus University, Denmark, has been leading a research partnership between Aarhus University, the University of Oxford and the University of Gothenburg, which has brought us one step closer to understanding the tactics used by viruses when they attack the immune system.Søren Riis Paludan heads a laboratory which carries out research into the immune system's ability to fight diseases caused by the herpes virus, influenza viruses and, most recently, SARS-CoV2, more commonly known as coronavirus.In the new study, which has just been published in the scientific journal "In the study, we found that the herpes simplex virus is capable of inhibiting a protein in the cells, known as STING, which is activated when there is a threat. When STING is inhibited, the body's immune system is also inhibited -- the virus thereby puts the brakes on the body's brake, which is supposed to prevent us from becoming ill. Other viruses also make use of the same principle," says Søren Riis Paludan.Søren Riis Paludan points out that though the study focuses on herpesviruses, there are parallels to the coronavirus. Interestingly, the same protein is also inhibited by many different viruses, including the coronavirus."This suggests that we have found an Achilles heel in the virus and the way it establishes infections in the body. Our results lead us to hope that if we can prevent viruses from blocking STING, then we can prevent the virus from replicating. That could pave the way for new principles for treatment of herpes, influenza and also the coronavirus," says Søren Riis Paludan.He hopes that the research results can be used in the development of antiviral drugs and vaccines in the future."Previous studies have also shown that the coronavirus inhibits STING in the same way as the herpes virus. This suggests that we have found a common denominator for several types of virus, and that this is probably an important element in the development of treatment," he says.

Microbes

May 19, 2020

https://www.sciencedaily.com/releases/2020/05/200519140401.htm

Emerging viral diseases causing serious issues in west Africa

In a new study, researchers from the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus call attention to the emergence of mosquito-borne viral outbreaks in West Africa, such as dengue (DENV), chikungunya (CHIKV) and Zika (ZIKV) viruses.

The findings are published in the current issue of "Emerging viruses are at the forefront of everyone's attention due to the COVID-19 pandemic. It has underscored the importance of preparing for and preventing large viral outbreaks that can have massive public health and economic consequences," said lead researcher Andrea Buchwald, PhD, a postdoctoral fellow in the Colorado School of Public Health.Buchwald adds, "We hope our research will prompt the development of early warning systems and adoption of control measures to prevent infectious outbreaks in West Africa. This will greatly impact the spread and severity of future outbreaks."The researchers reviewed 50 years of literature on arboviruses in West Africa to evaluate evidence of DENV, ZIKV and CHIKV and the distribution of their Aedes mosquito vectors in the region. This research delivers updates to previous estimates made, providing a current, region-specific synthesis of this rapidly evolving public health challenge."Large arboviral outbreaks will occur around the world. It is merely a question of where and when. Building awareness and surveillance capacity before the outbreaks occur can help detect outbreaks early and enable prompt and effective response to reduce health impacts," said Elizabeth Carlton, assistant professor of environmental and occupational health at the Colorado School of Public Health and co-author of the study.The researchers found that there is strong evidence that transmission of arboviral diseases including CHIKV, ZIKV and DENV is occurring in urban areas of West Africa and that the nature of transmission is distinct from the rural transmission of yellow fever virus that has historically been present in the region. The findings also provide evidence that the epidemiology of arboviral disease in West Africa has shifted and rapid urbanization and climate change have the potential to increase the risk of outbreaks in the future.Carlton adds, "Our study shows how urbanization and climate change can impact mosquito-borne virus transmission in West Africa. However, it also highlights the need for steps to be taken in the region to fill critical information gaps so that we can better define the spatial and temporal patterns of arboviral disease risk."The researchers outline some steps that can be taken to reduce the risk of major outbreaks, such as building testing capacity, investing in surveillance and implementing mosquito control measures.

Microbes

May 19, 2020

https://www.sciencedaily.com/releases/2020/05/200519090310.htm

How to improve the pneumococcus vaccine

Vaccines that protect people from infection by

This week in Current pneumococcal vaccines contain 10-13 different types of capsules, and they cause a person's immune system to produce antibodies against those capsules. "If you get rid of the capsules, then the bugs cannot cause the infection," Nahm said.But pneumococcus is a moving and constantly evolving target. As vaccines vanquish some capsules, new ones emerge that can shield the virus from the immune system. As a result, the vaccines become less effective, and the pathogen still poses a serious threat, even to immunized children. Nahm likened the pursuit of a pneumococcus vaccine to an ongoing game of whack-a-mole: Even as it protects people against known capsules, new ones pop up."Pneumococcus is smart," said Nahm. "It's critical for scientists to know about different capsule types." In the last decade or so, Nahm's lab in Birmingham -- recognized as a reference lab by the WHO -- has identified 10 new capsules. His research focuses on finding ways to make vaccines both more effective and less expensive. (The current pneumococcal vaccine costs about $100 per dose, putting it out of reach for many children in low-income countries.)Nahm and his collaborators discovered the new capsule after being contacted by the Global Pneumococcal Sequencing (GPS) project. With funding from the Bill and Melinda Gates Foundation, GPS researchers had sequenced the genomes of more than 20,000 pneumococci strains. When those researchers found strains with capsule genes they didn't recognize, they sent the strains to Nahm's group, which identified the new and 100th capsule structure.Notably, Nahm and his team discovered that some of the genes responsible for the new capsule came from oral streptococci, germs that live in the mouth and nose. Oral streptococci rarely cause diseases and are usually thought to be benign (though they can cause cavities). The connection suggests that the pathogenic pneumococci can capture advantageous genes from other, less harmful bacteria.That ability may help the pathogen hide even better in the body. Nahm said diagnostic tests will need to differentiate between the genes in benign bacteria, and those in streptococci. "We have to improve our diagnostic assays in the future to avoid false positives," he said. That connection may also affect vaccine research. "If we don't know which gene is coming from which species, then we could get the vaccine design wrong."

Microbes

May 18, 2020

https://www.sciencedaily.com/releases/2020/05/200518154937.htm

Cavity-causing bacteria assemble an army of protective microbes on human teeth

Studying bacteria in a petri dish or test tube has yielded insights into how they function and, in some cases, contribute to disease. But this approach leaves out crucial details about how bacteria act in the real world.

Taking a translational approach, researchers at the University of Pennsylvania School of Dental Medicine and the Georgia Institute of Technology imaged the bacteria that cause tooth decay in three dimensions in their natural environment, the sticky biofilm known as dental plaque formed on toddlers' teeth that were affected by cavities.The work, published in the journal "We started with these clinical samples, extracted teeth from children with severe tooth decay," says Hyun (Michel) Koo of Penn Dental Medicine, a co-senior author on the work. "The question that popped in our minds was, how these bacteria are organized and whether their specific architecture can tell us about the disease they cause?"To address this question, the researchers, including lead author Dongyeop Kim of Penn Dental Medicine and co-senior author Marvin Whiteley of Georgia Tech, used a combination of super-resolution confocal and scanning electron microscopy with computational analysis to dissect the arrangement of This approach, of understanding the locations and patterns of bacteria, is one that Whiteley has pursued in other diseases."It's clear that identifying the constituents of the human microbiome is not enough to understand their impact on human health," Whiteley says. "We also have to know how they are spatially organized. This is largely under studied as obtaining intact samples that maintain spatial structure is difficult."In the current work, the researchers discovered that "We found this highly ordered community with a dense accumulation of To learn more about how structure impacted the function of the biofilm, the research team attempted to recreate the natural plaque formations on a toothlike surface in the lab using "What we discovered, and what was exciting for us, is that the rotund areas perfectly matched with the demineralized and high acid levels on the enamel surface," says Koo. "This mirrors what clinicians see when they find dental caries: punctuated areas of decalcification known as 'white spots.' The domelike structure could explain how cavities get their start."In a final set of experiments, the team put the rotund community to the test, applying an antimicrobial treatment and observing how the bacteria fared. When the rotund structures were intact, the The study's findings may help researcher more effectively target the pathogenic core of dental biofilms but also have implications for other fields."It demonstrates that the spatial structure of the microbiome may mediate function and the disease outcome, which could be applicable to other medical fields dealing with polymicrobial infections," says Koo."It's not just which pathogens are there but how they're structured that tells you about the disease that they cause," adds Whiteley. "Bacteria are highly social creatures and have friends and enemies that dictate their behaviors."The field of microbial biogeography is young, the researchers say, but extending this demonstration that links community structure with disease onset opens up a vast array of possibilities for future medically relevant insights.Dongyeop Kim was a research associate at Penn's School of Dental Medicine's Department of Orthodontics and is now an assistant professor at the Jeonbuk National University (Korea).Hyun (Michel) Koo is a professor in Penn's School of Dental Medicine's Department of Orthodontics in the divisions of Community Oral Health and Pediatric Dentistry.Marvin Whiteley is a professor of biological sciences, the Georgia Tech Bennie H. and Nelson D. Abell Chair in Molecular and Cellular Biology, and the Georgia Research Alliance Eminent Scholar co-director in Emory-Children's CF Center at the Georgia Institute of Technology.Koo, Kim, and Whiteley's coauthors were Penn Dental Medicine's Rodrigo A. Arthur, Yuan Liu, Elizabeth L. Scisci, and Evlambia Hajishengallis; Georgia Tech's Juan P. Barraza; and Indiana University's Anderson Hara and Karl Lewis.The work was supported in part by the National Institute for Dental and Craniofacial Research (grants DE025220, DE018023, DE020100, and DE023193).

Microbes

May 18, 2020

https://www.sciencedaily.com/releases/2020/05/200518144919.htm

A new brick in the wall: Bacterial cell wall intermediate found

An accumulation of an unexpected intermediate of the peptidoglycan recycling pathway that is able to modulate the synthesis and structure of the cell wall, has been found by researchers at Umeå University, Sweden.

Most bacteria are shielded by a protective cell wall consisting of a strong yet elastic polymer called peptidoglycan. Peptidoglycan is essential for bacteria and so, it has always been in the spotlight when it comes to the development of antibiotics. Identifying new weaknesses of the bacterial cell wall as antibiotic targets is of highest international priority to fight pathogenic bacteria.As bacteria grow, the peptidoglycan needs to grow too. In order to insert new subunits, certain enzymes must open up the peptidoglycan mesh and, as a consequence, fragments known as muropeptides are released to the extracellular environment. During an infection, these muropeptides can be detected by the host as a "danger" signals, which induce a high immune response. Therefore, in order to survive inside the host many bacterial species have devised mechanisms to re-internalize these peptidoglycan fragments, a process known as peptidoglycan recycling. However, despite it is unquestionable its value in keeping bacteria away from the host radar, peptidoglycan recycling does not exclusively happen during infection and because of this, the true biological meaning of this process has remained mysterious for microbiologists.Felipe Cava's research group at the Molecular Infection Medicine Sweden (MIMS) studied the genetics and physiology behind the peptidoglycan-recycling pathway using as experimental model the causative agent of cholera, Vibrio cholerae. The study was performed in collaboration with Tobias Dörr (Cornell University, USA) and Matthew K. Waldor (Harvard Medical School, USA) and the results have been published in the journal The scientists have revealed an unnoticed link between peptidoglycan recycling and synthesis to promote optimal cell wall assembly and composition.The peptidoglycan recycling pathway is widely conserved amongst bacteria but this process seems to be not essential and its biological importance for the bacteria were not well-understood."Our lab found that the accumulation of an unexpected intermediate of the peptidoglycan recycling pathway is able to modulate the synthesis and structure of the cell wall; thus, our work provides new insights into the intersection between the peptidoglycan recycling and the de novo biosynthetic pathways," explained Felipe Cava, head of the study.Peptidoglycan recycling is accomplished by a sequence of enzymatic steps where reinternalized muropeptides are broken down into smaller pieces. A critical step in this process is carried out by L,D-carboxypeptidases, specific enzymes that remove the terminal D-amino acid of the muropeptides. The Cava lab has found that these enzymes represent the "control checkpoint" between peptidoglycan recycling and peptidoglycan synthesis."A few years ago our lab, together with other colleagues, discovered that under stress conditions V. cholerae is able to produce a set of unusual amino acids (named "non-canonical D-amino acids") such as, for instance, D-Methionine. In this study we have found that muropeptides modified with these non-canonical D-amino acids are poorly recycled by LD-carboxypeptidases thereby inducing the accumulation of intermediates which play an unforeseen role in regulating the synthesis and architecture of the cell wall," explains Sara Hernández, postdoctoral researcher who conducted the study.Besides the role in regulating cell wall synthesis and structure, extracellular peptidoglycan fragments are known to be important signals in innate immunity, organ development and behavior."Although most of the peptidoglycan fragments are recovered for recycling, under certain conditions bacteria can release them to the environment. It will be important to consider whether peptidoglycan fragments modified with non-canonical D-amino acids convey distinct information in inter-kingdom signaling compared to fragments with canonical chemistries," explained Felipe Cava, head of the study."Moreover, in microbial ecology, our findings suggest that the release the modified muropeptides into the environment could mediate interspecies peptidoglycan cross-regulation. Whether this regulation can promote cooperative or competitive behaviors is something that will need to be investigated in the future," concludes Felipe Cava.

Microbes

May 18, 2020

https://www.sciencedaily.com/releases/2020/05/200518111634.htm

Scientists inject proteins into eukaryontic cells

When bacteria such as

The T3SS is essential for virulence in many important human pathogens, including Consequently, the T3SS is considered a central target for potential therapeutics that could impair its function and prevent infections. On the other hand, hijacking this bacterial system would offer the chance for controlled protein delivery to host cells through the T3SS, like in a trojanic horse. Protein injection through T3SS is fast and efficient: a single injectisome can transfer several thousand effector proteins in few seconds.However, as powerful as the T3SS injection system is, it is far from accurate -- much to the disappointment of the researchers. "As soon as a T3SS contacts any host cell, it fires its load immediately. This is unfavourable for applications in biotechnology or medicine, where we want to target specific cell types, for example in tumour therapy," says Andreas Diepold, Research group leader at the Max-Planck-Institute for Terrestrial Microbiology in Marburg.But now Andreas Diepold and his team have come a big step closer to this goal: they succeeded in controlling the T3SS injectisome using a molecular light switch. This will enable scientists to inject proteins into eukaryotic cells at a precise time and place. "During my postdoctoral fellowship in Oxford, I discovered that some parts of the T3SS are dynamic," Andreas Diepold recalls. "They are constantly exchanged between this apparatus and the interior of the cell." The scientist applied his findings to the young research field of optogenetics. The principle of this technique is that protein interactions can be controlled with millisecond speed by changing their conformation when stimulated with light of specific wavelengths, thus allowing a fast and specific control of defined molecular processes in biological systems.Doctoral fellow Florian Lindner coupled the dynamic T3SS component with one part of this optogenetic interaction switch, while its other part was anchored to the bacterial membrane. By exposing bacteria and host cells to blue light, the availability of the T3SS components and consequently the function of the T3SS could be switched on and off.Since the system is flexible in regard to which kind of proteins are injected, it can be used in many ways. In a collaboration with Thorsten Stiewe from the Philipps University in Marburg, the research group used the new system to attack and kill cultured tumour cells. The group now plans to use this technique for future basic research and for the development of further application.

Microbes

May 14, 2020

https://www.sciencedaily.com/releases/2020/05/200514131710.htm

Can COVID-19 spread through fecal matter?

Early studies show evidence of COVID-19 genetic material in fecal matter, but more work is needed to determine if the virus can be spread through stool, according to a new review paper from a Rice University epidemiologist.

"Potential Fecal Transmission of SARS-CoV-2: Current Evidence and Implications for Public Health" will appear in an upcoming edition of the "Most of the studies that have been done so far are picking up viral RNA in the feces rather than infectious virus," said E. Susan Amirian, an epidemiologist with Rice's Texas Policy Lab and the study's lead author. "However, a few studies have showed that infectious virus may be present in stool samples."Amirian said the mere presence of genetic material is less worrisome than if infectious amounts of viable virus are found in stool in future studies, as that would imply it is possible for it to be transmitted to others through feces. She said if future research continues finding viable virus in stool, this could have important implications, especially for those working in the restaurant industry, nursing homes, day cares, etc."Ultimately, more research is needed to determine whether exposure to stool is spreading this virus and making the pandemic worse," Amirian said. "But given this possibility, it behooves us to be more careful, especially in settings where people have an increased risk of morbidity and death due to COVID-19."Amirian said there's no downside to exercising an abundance of caution in following good personal hygiene practices until we know more."There are plenty of other diseases out there that are transmitted through fecal contamination, including hepatitis A and norovirus," she said. "Following a high level of precaution will help just in case COVID-19 can be spread this way."

Microbes

May 14, 2020

https://www.sciencedaily.com/releases/2020/05/200514115834.htm

SARS lessons for COVID-19 vaccine design

Important lessons learned from the Severe Acute Respiratory Syndrome (SARS) outbreak of 2002-2003 could inform and guide vaccine design for COVID-19 according to University of Melbourne Professor Kanta Subbarao, Director of the WHO Centre for Reference and Research on Influenza at the Doherty Institute.

In an article published today in Neutralising antibodies prevent infection by binding to a virus and blocking their ability to infect. After an infection, a host can produce neutralising antibodies to protect against future infection."The speed with which SARS-CoV-2, the virus that causes COVID-19, has spread around the world and its toll in numbers of cases, severe illness, and death has been staggering," she said."However, technological advances have made rapid vaccine development possible. We have to ask ourselves what the new vaccines should aim to achieve -- prevent all infection or prevent severe disease and death? In which age group(s)? What effect will vaccines that address these choices have on subsequent epidemics?"Professor Subbarao was the Chief of the Emerging Respiratory Viruses Section of the Laboratory of Infectious Diseases at the National Institute for Allergy and Infectious Disease at the US National Institutes of Health during the SARS outbreak in 2002-2003, and was central to an important discovery of how neutralising antibodies protect from infection."We used mouse experiments to establish the very important principle that neutralising antibodies alone were sufficient to protect them from SARS-CoV infection," Professor Subbarao described.She also explained the crucial discovery that the 'spike' protein of the virus induced neutralising antibodies, and the importance of animal trials of several SARS vaccine candidates.Coronavirus particles have a corona (crown) of spike proteins that allow the virus to attach and enter cells."The 'spike' proteins of both SARS-CoV and SARS-CoV-2 are related and they attach to the same molecule called ACE 2 on human cells to infect people. We now also know through animal experiments with SARS-CoV-2 that neutralising antibodies protect from reinfection," Professor Subbarao said."Two SARS vaccines were evaluated in humans, and a number of promising candidates were tested in pre-clinical studies, but they weren't pursued because SARS didn't re-emerge."However, the work on SARS is relevant to the COVID-19 pandemic because the two viruses share several features and many of the principles and experience with SARS vaccines will apply to SARS-CoV-2."

Microbes

May 14, 2020

https://www.sciencedaily.com/releases/2020/05/200514115815.htm

One-two punch may help fight against Salmonella

McMaster University researchers have discovered a combination punch to treat drug-resistant infections that is showing promise based on testing in mice.

Researchers found that a natural product called dephostatin is an effective partner for the antibiotic colistin in treating infections caused by the bacteria Colistin is considered a last-resort antibiotic for multidrug-resistant bacterial infections due its toxic effect on the body, which has limited its use in medicine. However, when paired together, dephostatin allowed for drastically lower concentrations of colistin in a treatment regimen for The study details are published in "The rise of antibiotic resistance has ushered in the post-antibiotic age, and alternatives to antibiotics are urgently required," said Caressa Tsai, first author of the study and a PhD student in biochemistry and biomedical sciences in the Coombes lab at McMaster. "Solving the antibiotic resistance crisis will require us to shift away from the traditional view of antibiotic discovery."The World Health Organization has classified antibiotic-resistant In their study, researchers found that dephostatin does not kill While the initial findings were done using a method of experimentation called high-throughput screening, the researchers were excited to find that co-administering dephostatin and colistin in mice with a lethal By the numbers, treatment with colistin alone extended survival of almost 88 per cent of mice to approximately five days post infection and 25 per cent of mice survived to the end of the experiment. However, more than 62 per cent of mice treated with both dephostatin and colistin survived the infection, indicating a significant improvement over therapy with one antibiotic."Traditional antibiotics all work in a similar way -- they clear infections by killing bacteria," said Tsai. "Here, we were interested in a different approach -- keeping bacteria alive, but chemically inactivating important pathways to prevent them from causing infection."Researchers are continuing their research to understand how dephostatin works against "Dephostatin appears to knock out two important regulatory pathways that control "This research highlights the opportunities in taking a different approach than traditional antibiotic discovery and is enabling new drug combinations to emerge."The study is funded by the Canadian Institutes of Health Research and the Boris Family Fund for Health Research Excellence.

Microbes

May 14, 2020

https://www.sciencedaily.com/releases/2020/05/200514115736.htm

Global spread of the multi-resistant pathogen Stenotrophomonas maltophilia

An international consortium found a remarkable global spread of strains of a multi-resistant bacterium that can cause severe infections --

Scientists from a total of eight countries initially established a genotyping method that enables the standardised analysis of the different genomes of The scientists found that the Transmission analysis also identified several potential outbreak events of genetically closely related strains that were isolated within days or weeks in the same hospitals. "Combined with studies on other pathogens, our results show how systematic genome-based monitoring of

Microbes

May 14, 2020

https://www.sciencedaily.com/releases/2020/05/200514115411.htm

Researchers discover potential targets for COVID-19 therapy

A team of biochemists and virologists at Goethe University and the Frankfurt University Hospital were able to observe how human cells change upon infection with SARS-CoV-2, the virus causing COVID-19 in people. The scientists tested a series of compounds in laboratory models and found some which slowed down or stopped virus reproduction. These results now enable the search for an active substance to be narrowed down to a small number of already approved drugs. Based on these findings, a US company reports that it is preparing clinical trials. A Canadian company is also starting a clinical study with a different substance.

Since the start of February, the Medical Virology of the Frankfurt University Hospital has been in possession of a SARS-CoV-2 infection cell culture system. The Frankfurt scientists in Professor Sandra Ciesek's team succeeded in cultivating the virus in colon cells from swabs taken from two infected individuals returning from Wuhan (Hoehl Using a technique developed at the Institute for Biochemistry II at Goethe University Frankfurt, researchers from both institutions were together able to show how a SARS-CoV-2 infection changes the human host cells. The scientists used a particular form of mass spectrometry called the mePROD method, which they had developed only a few months previously. This method makes it possible to determine the amount and synthesis rate of thousands of proteins within a cell.The findings paint a picture of the progression of a SARS-CoV-2 infection: whilst many viruses shut down the host's protein production to the benefit of viral proteins, SARS-CoV-2 only slightly influences the protein production of the host cell, with the viral proteins appearing to be produced in competition to host cell proteins. Instead, a SARS-CoV-2 infection leads to an increased protein synthesis machinery in the cell. The researchers suspected this was a weak spot of the virus and were indeed able to significantly reduce virus reproduction using something known as translation inhibitors, which shut down protein production.Twenty-four hours after infection, the virus causes distinct changes to the composition of the host proteome: while cholesterol metabolism is reduced, activities in carbohydrate metabolism and in modification of RNA as protein precursors increase. In line with this, the scientists were successful in stopping virus reproduction in cultivated cells by applying inhibitors of these processes. Similar success was achieved by using a substance that inhibits the production of building blocks for the viral genome.The findings have already created a stir on the other side of the Atlantic: in keeping with common practise since the beginning of the corona crisis, the Frankfurt researchers made these findings immediately available on a preprint server and on the website of the Institute for Biochemistry II. Professor Ivan Dikic, Director of the Institute, comments: "Both the culture of 'open science', in which we share our scientific findings as quickly as possible, and the interdisciplinary collaboration between biochemists and virologists contributed to this success. This project started not even three months ago, and has already revealed new therapeutic approaches to COVID-19."Professor Sandra Ciesek, Director of the Institute for Medical Virology at the University Hospital Frankfurt, explains: "In a unique situation like this we also have to take new paths in research. An already existing cooperation between the Cinatl and Münch laboratories made it possible to quickly focus the research on SARS-CoV-2. The findings so far are a wonderful affirmation of this approach of cross-disciplinary collaborations."Among the substances that stopped viral reproduction in the cell culture system was 2-Deoxy-D-Glucose (2-DG), which interferes directly with the carbohydrate metabolism necessary for viral reproduction. The US company Moleculin Biotech possesses a substance called WP1122, a prodrug similar to 2-DG. Recently, Moleculin Biotech announced that they are preparing a clinical trial with this substance based on the results from Frankfurt.Based on another one of the substances tested in Frankfurt, Ribavirin, the Canadian company Bausch Health Americas is starting a clinical study with 50 participants.Dr Christian Münch, Head of the Protein Quality Control Group at the Institute for Biochemistry II and lead author, comments: "Thanks to the mePROD-technology we developed, we were for the first time able to trace the cellular changes upon infection over time and with high detail in our laboratory. We were obviously aware of the potential scope of our findings. However, they are based on a cell culture system and require further testing. The fact that our findings may now immediately trigger further in vivo studies with the purpose of drug development is definitely a great stroke of luck." Beyond this, there are also other potentially interesting candidates among the inhibitors tested, says Münch, some of which have already been approved for other indications.Professor Jindrich Cinatl from the Institute of Medical Virology and lead author explains: "The successful use of substances that are components of already approved drugs to combat SARS-CoV-2 is a great opportunity in the fight against the virus. These substances are already well characterised, and we know how they are tolerated by patients. This is why there is currently a global search for these types of substances. In the race against time, our work can now make an important contribution as to which directions promise the fastest success."

Microbes

May 14, 2020

https://www.sciencedaily.com/releases/2020/05/200514115847.htm

Decoding the massively complex gut microbiome

For something that has evolved with us over millions of years, and remains part of our physiology over our entire lives, our gut microbiome, oddly, remains somewhat of a mystery. Comprised of trillions of microbes of at least a thousand different species, this community of bacteria, viruses, protozoa and fungi in our gastrointestinal tracts is unique to each individual and has been found to be intimately connected to various fundamental aspects of our fitness, from our immunity to our metabolism and mental health.

For UC Santa Barbara researchers Eric Jones, Zipeng Wang and Joshua Mueller, the gut microbiome is a remarkable machine, full of interactions and competitions that directly impact our wellness. Tuning this machine in a favorable direction, they say, could improve our resistance to disease."Can medical therapies improve host health by modifying the microbiome composition? We still don't really know, so it's a huge field of research," Jones said. "This question is a great motivator."In our daily lives, many of us hope to improve our gut microbiome by taking probiotics and eating fermented foods. In clinical situations, fecal transplants have been shown to successfully treat recurring infections of the gut bacteria Clostridium difficile, which often recur after antibiotics used to treat infections wipe out "helpful" gut bacteria as well.But outside of sweeping and heroic measures to add populations of good bacteria to the GI tract, there isn't a whole lot known about how to subtly point the system in a healthy direction."It's about more than just putting in the right microbes," Jones said. "You need to understand the environment that the microbes are in and you need to understand what facilitates a stable gut microbiome composition."To tackle this problem, the researchers, under the guidance of UC Santa Barbara physics professor Jean Carlson, propose a technique for driving a mathematical gut microbiome model toward a target microbiome composition by manipulating certain parameters of the model. Called SPARC (SSR-guided parameter change), this approach reduces the complexity of the system without sacrificing it. And, according to a study published in the journal "So basically, the goal is to find a parameter change that corresponds to a change in the microbiome environment," said lead author Zipeng Wang. It helps to envision the gut microbiome as a ball perched on the top of a hill, poised to roll down in one direction or another. In this idealization, the gut environment dictates the shape of the hill. A healthy microbiome composition lies at the base of one side of the hill, and a disease-associated composition on the other. While fecal transplants directly push the ball to the healthy side of the hill, SPARC, according to the researchers, controls the shape of the hill, effectively rolling the ball down on one side or the other.To describe this gut ecosystem (data was collected from mouse model experiments at Memorial Sloan-Kettering Center in New York), the researchers used the generalized Lotka-Volterra (gLV) equations. Known also as predator-prey equations, the gLV equations stem from a century-old method used in traditional ecology to describe the interactions between species on Earth, such as competition and predation, as well as effects from indirect interactions."But, one of the difficulties is that the gut microbiome has all these different bacterial species," Wang said, "So the Lotka-Volterra equations become very high-dimensional, which means that there are a lot of parameters, and a lot of different ways for bacteria to interact with one another. It would be very hard for us to find the right parameters to achieve the desired microbiome composition."To avoid the trial-and-error of manipulating an unwieldy number of different parameters, the team opted instead to examine a compressed but reliable 2D representation of the ecological model generated by the dimensionality reduction technique called "steady state reduction" (SSR). According to the researchers, this allowed them to zoom out and identify the key parameters that control the shape of the hill."What we like about our model is that it gives us a systematic strategy to identify these low-dimensional features that are really sensitive, that are the most important," Jones explained. "I was really surprised and pleased that we could, for example, find a single parameter and change it by 10% of its value and that would change the shape of the hill."What is that parameter? Well, given the diversity of gut microbiomes, diets, co-occurring conditions and environmental influences, there is not necessarily one universal parameter change -- say, acidity, or fiber content -- that fits all. The SPARC method, the researchers say, guides thinking on how to identify the significant parameters based on data.In addition, SPARC currently is primarily a mathematical exercise, though the researchers are eager to try it out in an experimental setting."There are people working on what they call gut-on-a-chip systems, which are kind of like miniature Petri dishes that replicate some of the conditions of the human gut microbiome," said Joshua Mueller. "It would be really exciting to validate SPARC in these tightly controlled experimental circumstances."In the rather more distant future, Jones said, this method could also help pave the way for personalized microbiome management, in which real-time readouts of the state of our microbiomes -- say, from a smart toilet -- could tell us to change our dietary habits to avoid illness and improve our general well-being."In order to get to that point, we need mechanistic models of the microbiome," he said. "We need to understand how to control it. We need to understand how environmental feedbacks play into microbial dynamics."

Microbes

May 13, 2020

https://www.sciencedaily.com/releases/2020/05/200513171117.htm

Microbiome therapy protects against recurrent bacterial vaginosis

A product containing healthy vaginal bacteria has proved effective against recurrent bacterial vaginosis (BV), an extremely common vaginal infection that is associated with preterm birth, HIV infection and problems with

Bacterial vaginosis is one of the most frequent bacterial infections, affecting nearly 30 percent of women of reproductive age in the United States, and anywhere from 15 to 50 percent of women around the world. It is associated with the spread of HIV in Africa, where women make up the majority of those infected, as well as preterm birth and low-birth weight around the world.The findings, published Wednesday, May 13, 2020, in the The randomized, placebo-controlled, double-blind trial showed a significant reduction in the recurrence of BV and found no safety risks from the bacteria used in the LACTIN-V formulation of the species Lactobacillus crispatus CTV-05, a common bacterium found in healthy vaginal microbiomes.While BV is commonly treated with an antibiotic called metronidazole, up to three-quarters of women get the infection again within three months. The study found that LACTIN-V reduced these recurrences significantly. Just 30 percent of women who were given LACTIN-V after initial antibiotic treatment had a recurrence within 12 weeks, compared to 45 percent of the women who received the antibiotic and a placebo.LACTIN-V, which is produced by Osel, Inc. of Mountain View, Calif., comes in a powder form that women self-administer with a vaginal applicator. Once the healthy bacteria in the powder colonize the vagina, they produce lactic acid, which inhibits the growth of bacteria associated with BV. LACTIN-V is stable for more than a year at room temperature, and more than two years in the refrigerator.The 228 women in the trial used LACTIN-V once a day for five days, and then twice a week for 10 weeks. Researchers said the product's ease of use could make it an ideal medication for women around the world."The initial indication for LACTIN-V is for the prevention of BV, which millions of women in the U.S. have each year," said first author of the paper and study lead Craig Cohen, MD, professor of obstetrics, gynecology and reproductive sciences at UCSF. "But this product also has the potential to be an effective intervention to prevent HIV infection and preterm birth."Before LACTIN-V can be used, however, the U.S. Food and Drug Administration (FDA) is likely to require a successful Phase III trial with more participants."This is an entirely new approach that strengthens the vaginal microbiome against infections," said Anke Hemmerling, MD, PhD, MPH, a researcher at UCSF and the senior author of the new study. "This could be a breakthrough for the long-term prevention of BV."

Microbes

May 13, 2020

https://www.sciencedaily.com/releases/2020/05/200513143353.htm

Dynamics of gut bacteria follow ecological laws

The seemingly chaotic bacterial soup of the gut microbiome is more organized than it first appears and follows some of the same ecological laws that apply to birds, fish, tropical rainforests, and even complex economic and financial markets, according to a new paper in

One of the main challenges facing researchers who study the gut microbiome is its sheer size and amazing organizational complexity. Many trillions of bacteria, representing thousands of different species, live in the human intestinal tract, interacting with each other and the environment in countless and constantly changing ways.The study's discovery of multiple principles of gut bacterial dynamics should help researchers to understand what makes a gut microbiome healthy, how it may become perturbed in disease and unhealthy diets, and also suggest ways we could alter microbiomes to improve health.Although current DNA sequencing technologies make it possible to identify and track bacteria in the gut over time, "the biological processes governing the short- and long-term changes in the gut's microbiome remain very poorly understood," says the study's senior author, Dennis Vitkup, PhD, associate professor of systems biology and of biomedical informatics at Columbia University Vagelos College of Physicians and Surgeons.As a first step in identifying the factors that describe microbial communities in the gut, Vitkup and his co-authors, graduate students Brian W. Ji and Ravi U. Sheth and research scientists Purushottam Dixit and Konstantine Tchourine, looked for mathematical relationships describing dynamical changes of the gut microbiome of four healthy people followed for a year. They also analyzed microbiome data obtained for mice fed either high fiber or high fat diets every day for several weeks.With this data, the researchers explored statistical connections between various aspects of microbiome dynamics, such as fluctuations and abundances of various bacteria over time, or the average times different microbes continuously reside in the human gut. "Up to now, it has been an open question whether there are any natural laws describing dynamics of these complex bacterial communities," Vitkup says.As expected, they discovered large fluctuations in the composition and daily changes of the human and mouse gut microbiomes. But strikingly, these apparently chaotic fluctuations followed several elegant ecological laws."Similar to many animal ecologies and complex financial markets, a healthy gut microbiome is never truly at equilibrium," Vitkup says. "For example, the number of a particular bacterial species on day one is never the same on day two, and so on. It constantly fluctuates, like stocks in a financial market or number of animals in a valley, but these fluctuations are not arbitrary. In fact, they follow predictable patterns described by Taylor's power law, a well-established principle in animal ecology that describe how fluctuations are related to the relative number of bacteria for different species."Other discovered laws of the gut microbiome also followed principles frequently observed in animal ecologies and economic systems, including the tendency of gut bacteria abundances to slowly but predictably drift over time and the tendency of species to appear and disappear from the gut microbiome at predictable times."It is amazing that microscopic biological communities -- which are about six orders of magnitude smaller than macroscopic ecosystems analyzed previously -- appear to be governed by a similar set of mathematical and statistical principles," says Vitkup.These universal principles should help researchers to better understand what processes govern the microbial dynamics in the gut. Using the statistical laws, the Columbia researchers were able to identify particular bacterial species with abnormal fluctuations. These wildly fluctuating bacteria were associated with documented periods of gut distress or travel to foreign countries in humans providing data for the study. Thus, this approach may immediately allow researchers to understand and identify which specific bacteria are out of line and behave in a potentially harmful fashion.Using mice data, the researchers also observed that microbiomes associated with unhealthy high fat diets drift in time significantly faster compared with microbiomes feeding on healthier high fiber diets. This demonstrates that ecological laws can be applied to understand how various dietary changes may affect and perhaps alleviate persistent microbiome instabilities.The study by Columbia researchers also opens an exciting opportunity to use the gut microbial communities as a model system for exploring general ecological relationships. "Ecologists have debated for years why and how these natural ecological laws arise, without any clear answers," says Vitkup. "Previous ecological research has been mostly limited to observational studies, which can take decades to perform for animals and plants. And some key experiments, such as additions or removal of particular species simply cannot be performed."The gut microbiome, in contrast, provides an ideal miniature laboratory, where researchers could easily manipulate different variables, such as the number and composition of microorganisms, and then explore various aspects of environmental influences. "One of our next goals is to understand the origin of these general ecological laws using gut microbiota," Vitkup says.

Microbes

May 12, 2020

https://www.sciencedaily.com/releases/2020/05/200512151955.htm

Marine waste management: Recycling efficiency by marine microbes

A team of researchers from the Biology Centre Czech Academy of Sciences (Budweis, Czechia), MARUM -- Center for Marine Environmental Sciences at the University of Bremen (Germany), and Max Planck Institute for Marine Microbiology (Bremen, Germany) have estimated that these chemoautotrophs recycle approximately 5 per cent of the carbon and phosphorus assimilated by marine algae and release terragrams (1012 g) of dissolved organics to the ocean interior each year. These findings are now published in the journal

The widespread success of marine thaumarchaea arises largely from their ability to convert trace concentrations of ammonia to nitrite, which gives them energy to fix carbon and produce new biomass in the absence of light. This process, termed nitrification, recycles the chemical energy originally derived from photosynthesis by marine algae and is an essential component of global nutrient cycling. Using a radiotracer approach, the collaborative research effort has now determined that archaea fix roughly 3 moles of carbon for every 10 moles of ammonia oxidized and this efficiency varies with cellular adaptations to phosphorus limitation. "Thaumarchaea are active throughout the ocean, and their vast numbers imply significant contributions to global cycles of carbon (C) and nitrogen (N)," says Travis Meador, who is lead author of the study and had received a grant by the German Research Foundation (Deutsche Forschungsgemeinschaft DFG) to perform this work during his time at MARUM. "Just how much carbon is fixed by nitrifiers is regulated by the amount of organic nitrogen (energy) that is created during photosynthesis, the physiological coupling of nitrification and carbon-assimilation, and also apparently their ability access to phosphorus (P)."Ammonia in the ocean derives from the breakdown of organic matter produced by phototrophs in surface waters and is a valuable source of energy and nutrition for Eukarya, Bacteria, and Archaea alike. Culture studies of the thaumarchaeon Nitrosopumilus maritimus have previously revealed that the tiny cells (Ø = 0.17-0.22 ?m) boast enzyme systems to achieve a high affinity for ammonia and the most energy-efficient C-fixation pathway in the presence of oxygen. "These adaptations make thaumarchaea the oceans' foremost energy recycler, allowing them to outcompete their bacterial counterparts and create a separate niche, particularly in the deep ocean where energy is limiting," Meador said. "Our colleagues have suggested that most organic N that is exported below the ocean's euphotic zone eventually fuels nitrification by thaumarchaea. While the global export flux has been investigated for several decades, there has been no empirical evidence to further couple archaeal ammonia oxidation to global rates of C-fixation, until now."In addition to their important contributions to chemical fluxes in the dark ocean chemical, thaumarchaea are actually more abundant in the euphotic zone, where the majority of organic matter is respired (to COThis zone, known as the thermocline, also experiences large fluctuations in the concentration and turnover time of another key nutrient, phosphate (P). The researchers thus questioned if thaumarchaeal access to phosphate may control their contributions to recycled production in the surface ocean.By introducing radiolabeled 14C-bicarbonate and 33P-phosphate to the culture medium, the authors could track the rates of C and P assimilated into N. maritimus cells and released as dissolved organic carbon and phosphorus (DOC and DOP) metabolites into culture media. Normalizing these rates to nitrification, the researchers generated the first estimates of C-, P-, DOC-, and DOP- yields for a marine archaeon.The upshot of this work is that global rates of C-fixation by widely-distributed thaumarchaea are likely at least 3-fold higher than previously assumed. Also, C- and P-assimilation by marine archaea may now be modeled as directly proportional to the renowned remineralization ratio established by Alfred Redfield in the mid-20th century. The researchers further found that N. maritimus is apt at acquiring phosphate, but strategic increases in cellular phosphate affinity came at a cost of approximately 30 per cent reduction in C-fixation efficiency. These results may therefore explain the widely ranging values of specific nitrification rate observed across the surface ocean. Finally, Meador portends that "the release of chemosynthetically manufactured compounds by thaumarchaea is minor compared to the substantial reservoir of dissolved organic nutrients in the ocean, but it does represent a fresh flux of labile substrates throughout the ocean interior."

Microbes

May 11, 2020

https://www.sciencedaily.com/releases/2020/05/200511154858.htm

The microbiome controls immune system fitness

Working alongside colleagues in Mainz, Bern, Hannover and Bonn, researchers from Charité -- Universitätsmedizin Berlin, the Berlin Institute of Health (BIH) and the German Rheumatism Research Center Berlin (DRFZ) were able to show how the microbiome helps to render the immune system capable of responding to pathogens. If absent, relevant mediators are not released, resulting in a failure to activate metabolic processes in certain immune cells. According to the researchers' report, which has been published in

Residing in environmental interfaces, the body's epithelial tissues represent potential gateways for pathogens. These tissues are also naturally colonized by a complex community of bacteria, viruses, fungi and parasites, and this is known as the microbiome. It is likely that, during the course of evolution, permanent interactions with these microorganisms resulted in the development of robust signaling pathways which help to protect the body. A team of researchers led by Prof. Dr. Andreas Diefenbach, Director of Charité's Institute of Microbiology, Infectious Diseases and Immunology, have been studying the microbiome's role in the body's immune response against harmful pathogens and the resulting effects on signaling pathways.Presence of an infection triggers the body's immune response. A key role in this process is played by 'conventional dendritic cells' (cDCs). These form part of the body's innate immune system and carry a range of pattern recognition receptors, which enable them to quickly detect invading pathogens. The cells' initial response involves the release of cytokines, signaling proteins which attract immune cells to the site of infection. At the same time, these cells also use phagocytosis to engulf and digest invasive pathogens, after which they present individual particles as antigens on their cell surface. This, in turn, leads to the activation of T cells (which form part of the adaptive immune system) and results in a targeted immune response. In contrast, when T cell activation is triggered by cDCs presenting endogenous antigens, this leads to a faulty and undesirable immune response and results in autoimmune diseases.The team of researchers led by Prof. Diefenbach found that cDCs are incapable of triggering immune responses in sterile conditions (i.e., in germ-free mice). The researchers concluded that cDCs must receive information while the cell is in its 'basal state' (which is characterized by the absence of infection) and that this information must derive from the microbiome. These microbiome-derived signals prime cDCs for a future response against pathogens. "We want to understand the nature of the microbiome's continuous effects on cDC function," says Prof. Diefenbach, who also holds an Einstein Professorship in Microbiology and leads the DRFZ's Mucosal Immunology Research Group. "In this study, we were able to show that, in their basal state, these specialist immune cells are subject to the uninterrupted microbiome-controlled signaling of type I interferons (IFN-I)." Interferons are cytokines, i.e. special signaling molecules which are known to play a role in antiviral activity. "Until now, we had known only little about the role of IFN-I in the basal state. cDCs, which do not receive this IFN-I signaling during the basal state, cannot fulfill the physiological functions which they perform as part of the body's fight against pathogens," explains the microbiologist. Study results suggest that the microbiome controls our immune system's fitness. It exerts this control by bringing the immune system to a state of 'readiness' in order to speed up its response to pathogens.The researchers used various animal models in order to gain insight into the manner in which the microbiome-controlled IFN-I primes basal-state cDCs for future combat. Using sequencing technology, the researchers were able to compare the epigenomes and transcriptomes of cDCs from germ-free animals with those of control animals and animals deficient in IFN-I receptors. The researchers wanted to know what happens at the molecular level in cDCs when they are no longer exposed to IFN-I. Describing the researchers' observations, the study's first author, Laura Schaupp, says: "Interestingly, when we looked at cDCs from germ-free animals and those without IFN-I signaling, we were able to observe low levels of expression among genes involved in the mitochondrial respiratory chain." The Charité researcher adds: "Further analyses revealed that the cellular metabolism of cDCs from germ-free animals is dysfunctional, making them unable to initiate an immune response. The cells effectively lack the fuel needed to respond to pathogens." This suggests that the microbiome is of crucial importance to the functioning of cDCs. It appears essential to the ability of cDCs to mount an effective response to bacterial or viral infections, including responses mediated by T cells.The researchers' findings may contribute to the development of new therapeutic approaches. Many autoimmune diseases, such as systemic lupus erythematosus, are caused by an increased production of IFN-I. Other studies have shown that the microbiome influences the effectiveness of checkpoint inhibitors in cancer immunotherapies. "These phenomena will continue to be of great interest to us," says Prof. Diefenbach. "For instance, is it possible to change the composition of the microbiome in such a way as to reduce the availability of IFN-I, thereby exerting a positive influence on autoimmune diseases? Or might it be possible to improve responses to cancer immunotherapies by exerting a positive influence on the underlying IFN-I production?" The team of researchers now plan to conduct further studies which will explore these questions.The principal partners involved in the research were Prof. Dr. Hansjörg Schild, Dr. Hans Christian Probst and Dr. Sabine Muth of the Institute for Immunology/Research Center for Immunotherapy, University Medical Center Mainz. Other key partners were Prof. Dr. Stephanie Ganal-Vonarburg and Prof. Dr. Andrew Macpherson in Bern. Dr. Mir-Farzin Mashreghi of the German Rheumatism Research Center Berlin (DRFZ) was responsible for RNA sequencing. Other important partners included Prof. Stefan Lienenklaus and Prof. Dr. Ulrich Kalinke of the Hanover Medical School (MHH). Epigenome analyses were performed in collaboration with Dr. Thomas Manke of the Max Planck Institute of Immunobiology and Epigenetics in Freiburg. Metabolic analyses were performed in collaboration with Dr. Christoph Wilhelm of the Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn. The study received substantial funding from the European Research Council (A. Diefenbach) and the German Research Foundation (A. Diefenbach, H.C. Probst and H. Schild).

Microbes

May 11, 2020

https://www.sciencedaily.com/releases/2020/05/200511142202.htm

A close relative of SARS-CoV-2 found in bats offers more evidence it evolved naturally

There is ongoing debate among policymakers and the general public about where SARS-CoV-2, the virus that causes COVID-19, came from. While researchers consider bats the most likely natural hosts for SARS-CoV-2, the origins of the virus are still unclear.

On May 10 in the journal "Since the discovery of SARS-CoV-2 there have been a number of unfounded suggestions that the virus has a laboratory origin," says senior author Weifeng Shi, director and professor at the Institute of Pathogen Biology at Shandong First Medical University in China. "In particular, it has been proposed the S1/S2 insertion is highly unusual and perhaps indicative of laboratory manipulation. Our paper shows very clearly that these events occur naturally in wildlife. This provides strong evidence against SARS-CoV-2 being a laboratory escape."The researchers identified RmYN02 from an analysis of 227 bat samples collected in Yunnan province, China, between May and October of 2019. "Since the discovery that bats were the reservoir of SARS coronavirus in 2005, there has been great interest in bats as reservoir species for infectious diseases, particularly as they carry a very high diversity of RNA viruses, including coronaviruses," Shi says. RNA from the samples was sent for metagenomic next-generation sequencing in early January 2020, soon after the discovery of SARS-CoV-2.Across the whole genome, the closest relative to SARS-CoV-2 is another virus, called RaTG13, which was previously identified from bats in Yunnan province. But RmYN02, the virus newly discovered here, is even more closely related to SARS-CoV-2 in some parts of the genome, including in the longest encoding section of the genome called 1ab, where they share 97.2% of their RNA. The researchers note that RmYN02 does not closely resemble SAR-CoV-2 in the region of the genome that encodes the key receptor binding domain that binds to the human ACE2 receptor that SARS-CoV-2 uses to infect host cells. This means it's not likely to infect human cells.The key similarity between SARS-CoV-2 and RmYN02, is the finding that RmYN02 also contains amino acid insertions at the point where the two subunits of its spike protein meet. SARS-CoV-2 is characterized by a four-amino-acid insertion at the junction of S1 and S2; this insertion is unique to the virus and has been present in all SARS-CoV-2 sequenced so far. The insertions in RmYN02 are not the same as those in SARS-CoV-2, which indicates that they occurred through independent insertion events. But a similar insertion event happening in a virus identified in bats strongly suggests that these kinds of insertions are of natural origin. "Our findings suggest that these insertion events that initially appeared to be very unusual can, in fact, occur naturally in animal betacoronaviruses," Shi says."Our work sheds more light on the evolutionary ancestry of SARS-CoV-2," he adds. "Neither RaTG13 nor RmYN02 is the direct ancestor of SARS-CoV-2, because there is still an evolutionary gap between these viruses. But our study strongly suggests that sampling of more wildlife species will reveal viruses that are even more closely related to SARS-CoV-2 and perhaps even its direct ancestors, which will tell us a great deal about how this virus emerged in humans."This work was supported by the Academic Promotion Programme of Shandong First Medical University, the Strategic Priority Research Programme of the Chinese Academy of Sciences, the Chinese National Natural Science Foundation, the National Major Project for Control and Prevention of Infectious Disease in China, the High-End Foreign Experts Program of Yunnan Province, the Taishan Scholars Programme of Shandong Province, the NSFC Outstanding Young Scholars, Youth Innovation Promotion Association of CAS, and an ARC Australian Laureate Fellowship.

Microbes