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May 11, 2020

https://www.sciencedaily.com/releases/2020/05/200511112609.htm

New HIV vaccine strategy strengthens, lengthens immunity in primates

Investigators at the Stanford University School of Medicine and several other institutions have shown that a new type of vaccination can substantially enhance and sustain protection from HIV.

A paper describing the vaccine, which was given to monkeys, will be published online May 11 in The key to the new vaccine's markedly improved protection from viral infection is its ability -- unlike almost all vaccines now in use -- to awaken a part of the immune system that most current vaccines leave sleeping."Most vaccines aim at stimulating serum immunity by raising antibodies to the invading pathogen," said Pulendran, referring to antibodies circulating in blood. "This vaccine also boosted cellular immunity, the mustering of an army of immune cells that chase down cells infected by the pathogen. We created a synergy between these two kinds of immune activity."Pulendran, the Violetta L. Horton Professor II, shares senior authorship of the study with Rama Amara, PhD, professor of microbiology and immunology at Yerkes Primate Research Center at Emory University; Eric Hunter, PhD, and Cynthia Derdeyn, PhD, professors of pathology and lab medicine at Emory; and David Masopust, PhD, professor of microbiology and immunology at the University of Minnesota. The lead authors are Prabhu Arunachalam, PhD, a postdoctoral scholar at Stanford; postdoctoral scholars Tysheena Charles, PhD, and Satish Bollimpelli, PhD, of Emory; and postdoctoral scholar Vineet Joag, PhD, of the University of Minnesota.Some 38 million people worldwide are living with AIDS, the once inevitably fatal disease caused by HIV. While HIV can be held in check by a mix of antiviral agents, it continues to infect 1.7 million people annually and is the cause of some 770,000 deaths each year."Despite over three decades of intense research, no preventive HIV vaccine is yet in sight," Pulendran said. Early hopes for such a vaccine, based on a trial in Thailand whose results were published in 2012, were dashed just months ago when a larger trial of the same vaccine in South Africa was stopped after a preliminary assessment indicated that it barely worked.Vaccines are designed to arouse the adaptive immune system, which responds by generating cells and molecular weaponry that target a particular pathogen, as opposed to firing willy-nilly at anything that moves.The adaptive immune response consists of two arms: serum immunity, in which B cells secrete antibodies that can glom onto and neutralize a microbial pathogen; and cellular immunity, in which killer T cells roam through the body inspecting tissues for signs of viruses and, upon finding them, destroying the cells that harbor them.But most vaccines push the adaptive immune system to fight off infections with one of those arms tied behind its back."All licensed vaccines to date work by inducing antibodies that neutralize a virus. But inducing and maintaining a high enough level of neutralizing antibodies against HIV is a demanding task," Pulendran said. "We've shown that by stimulating the cellular arm of the immune system, you can get stronger protection against HIV even with much lower levels of neutralizing antibodies."In the new study, he and his colleagues employed a two-armed approach geared toward stimulating both serum and cellular immunity. They inoculated three groups of 15 rhesus macaques over a 40-week period. The first group received several sequential inoculations of Env, a protein on the virus's outer surface that's known to stimulate antibody production, plus an adjuvant, a chemical combination often used in vaccines to beef up overall immune response. The second group was similarly inoculated but received additional injections of three different kinds of viruses, each modified to be infectious but not dangerous. Each modified virus contained an added gene for a viral protein, Gag, that's known to stimulate cellular immunity.A third group, the control group, received injections containing only the adjuvant.At the end of the 40-week regimen, all animals were allowed to rest for an additional 40 weeks, then given booster shots of just the Env inoculation. After another rest of four weeks, they were subjected to 10 weekly exposures to SHIV, the simian version of HIV.Monkeys who received only the adjuvant became infected. Animals in both the Env and Env-plus-Gag groups experienced significant initial protection from viral infection. Notably, though, several Env-plus-Gag animals -- but none of the Env animals -- remained uninfected even though they lacked robust levels of neutralizing antibodies. Vaccinologists generally have considered the serum immune response -- the raising of neutralizing antibodies -- to be the defining source of a vaccine's effectiveness.Even more noteworthy was a pronounced increase in the duration of protection among animals getting the Env-plus-Gag combination. Following a 20-week break, six monkeys from the Env group and six from the Env-plus-Gag group received additional exposures to SHIV. This time, four of the Env-plus-Gag animals, but only one of the Env-only animals, remained uninfected.Pulendran said he suspects this improvement resulted from the vaccine-stimulated production of immune cells called tissue-resident memory T cells. These cells migrate to the site where the virus enters the body, he said, and park themselves there for a sustained period, serving as sentinels. If they see the virus again, these cells jump into action, secreting factors that signal other immune-cell types in the vicinity to turn the tissue into hostile territory for the virus."These results suggest that future vaccination efforts should focus on strategies that elicit both cellular and neutralizing-antibody response, which might provide superior protection against not only HIV but other pathogens such as tuberculosis, malaria, the hepatitis C virus, influenza and the pandemic coronavirus strain as well," Pulendran said.

Microbes

May 11, 2020

https://www.sciencedaily.com/releases/2020/05/200511092933.htm

Even animals benefit from social distance to prevent disease, research shows

Microorganisms living inside and on our body play a crucial role in both the maintenance of our health and the development of disease. Now researchers at UTSA have uncovered evidence about the importance of maintaining physical distance to minimize the spread of microbes among individuals.

The scientists observed monkeys in the wild to understand what role genetics, diet, social groupings and distance in a social network play when it comes to the microbes found inside an animal's gut."Social microbial transmission among monkeys can help inform us about how diseases spread. This has parallels to our current situation in which we are trying to understand how social distancing during the COVID 19 pandemic and future disease outbreaks may influence disease transmission," said Eva Wikberg, an assistant professor in UTSA's Department of Anthropology who studies the interaction between ecology, behavior and genetics in primates.The gut microbiome refers to all the microorganisms inhabiting the digestive tract, starting with the stomach and ending with the colon. Over the past decade the microbiome has come under more scientific focus because it's believed that an unhealthy gut microbiome can lead to obesity, impaired immune function, weakened parasite resistance and even behavioral changes.However, researching microbiomes is difficult because of the variation in microbial composition between individuals. One long-standing question is whether this variation is driven by genetic makeup, diets or social environments.This research inquiry has been especially hard in wild populations because of the lack of detailed data necessary to tease apart the myriad factors that shape the microbiome.To find an answer, Wikberg and fellow researchers studied the fecal matter of 45 female colobus monkeys that congregated in eight different social groups in a small forest by the villages of Boabeng and Fiema in Ghana. The scientists saw major differences among social groups' gut microbiomes.However, individuals from different groups that were more closely connected in the population's social network had more similar gut microbiomes. This discovery indicates that microbes may be transmitted during occasional encounters with members of other social groups.A similar setting may be when people come into one-meter proximity of each other at a store. Being in close proximity or accidentally brushing up against someone else may be all it takes to transmit certain microbes.This study suggests that microbes transmitted this way help the colobus monkeys digest the leaves in their diet. However, further research is needed to investigate whether this type of transmission yields health benefits, which could explain why different social groups occasionally have friendly between-group encounters."Studies of wild animals can teach us a lot about the importance of using interventions, such as social distancing, to ensure a safer community during this pandemic," said Wikberg.The study's findings are reported in the May issue of the journal Wikberg's other research collaborators are Diana Christie and Nelson Ting, of the Institute of Ecology and Evolution at the University of Oregon, and Pascale Sicotte, of the Department of Anthropology and Archaeology at the University of Calgary.

Microbes

May 8, 2020

https://www.sciencedaily.com/releases/2020/05/200508184604.htm

Individualized mosaics of microbial strains transfer from the maternal to the infant gut

Microbial communities in the intestine -- also known as the gut microbiome -- are vital for human digestion, metabolism and resistance to colonization by pathogens. The gut microbiome composition in infants and toddlers changes extensively in the first three years of life. But where do those microbes come from in the first place?

Scientists have long been able to analyze the gut microbiome at the level of the 500 to 1,000 different bacterial species that mainly have a beneficial influence; only more recently have they been able to identify individual strains within a single species using powerful genomic tools and supercomputers that analyze massive amounts of genetic data.Researchers at the University of Alabama at Birmingham now have used their microbiome "fingerprint" method to report that an individualized mosaic of microbial strains is transmitted to the infant gut microbiome from a mother giving birth through vaginal delivery. They detailed this transmission by analyzing existing metagenomic databases of fecal samples from mother-infant pairs, as well as analyzing mouse dam and pup transmission in a germ-free, or gnotobiotic, mouse model at UAB, where the dams were inoculated with human fecal microbes."The results of our analysis demonstrate that multiple strains of maternal microbes -- some that are not abundant in the maternal fecal community -- can be transmitted during birth to establish a diverse infant gut microbial community," said Casey Morrow, Ph.D., professor emeritus in UAB's Department of Cell, Developmental and Integrative Biology. "Our analysis provides new insights into the origin of microbial strains in the complex infant microbial community."The study used a strain-tracking bioinformatics tool previously developed at UAB, called Window-based Single-nucleotide-variant Similarity, or WSS. Hyunmin Koo, Ph.D., UAB Department of Genetics and Genomics Core, led the informatics analysis. The gnotobiotic mouse model studies were led by Braden McFarland, Ph.D., assistant professor in the UAB Department of Cell, Developmental and Integrative Biology.Morrow and colleagues have used this microbe fingerprint tool in several previous strain-tracking studies. In 2017, they found that fecal donor microbes -- used to treat patients with recurrent Clostridium difficile infections -- remained in recipients for months or years after fecal transplants. In 2018, they showed that changes in the upper gastrointestinal tract through obesity surgery led to the emergence of new strains of microbes. In 2019, they analyzed the stability of new strains in individuals after antibiotic treatments, and earlier this year, they found that adult twins, ages 36 to 80 years old, shared a certain strain or strains between each pair for periods of years, and even decades, after they began living apart from each other.In the current study, several individual-specific patterns of microbial strain-sharing were found between mothers and infants. Three mother-infant pairs showed only related strains, while a dozen other infants of mother-infant pairs contained a mosaic of maternal-related and unrelated microbes. It could be that the unrelated strains came from the mother, but they had not been the dominant strain of that species in the mother, and so had not been detected.Indeed, in a second study using a dataset from nine women taken at different times in their pregnancies showed that strain variations in individual species occurred in seven of the women.To further define the source of the unrelated strains, a mouse model was used to look at transmission from dam to pup in the absence of environmental microbes. Five different females were given transplants of different human fecal matter to create five unique humanized-microbiome mice, which were bred with gnotobiotic males. The researchers then analyzed the strains found in the human donors, the mouse dams and their mouse pups. They found four different patterns: 1) The pup's strain of a particular species was related to the dam's strain; 2) The pup's strain was related to both the dam's strain and the human donor's strain; 3) The pup's strain was related to the human donor's strain, but not to the dam's strain; and, importantly, 4) No related strains for a particular species were found between the pup, the dam and the human donor. Since these animals were bred and raised in germ-free conditions, the unrelated strains in the pups came from minor, undetected strains in the dams."The results of our studies support a reconsideration of the contribution of different maternal microbes to the infant enteric microbial community," Morrow said. "The constellation of microbial strains that we detected in the infants inherited from the mother was different in each mother-infant pair. Given the recognized role of the microbiome in metabolic diseases such as obesity and type 2 diabetes, the results of our study could help to further explain the susceptibility of the infant to metabolic disease found in the mother."

Microbes

May 8, 2020

https://www.sciencedaily.com/releases/2020/05/200508083534.htm

Pangolins may possess evolutionary advantage against coronavirus

Similar to how a smoke detector sounds off an alarm, certain genes sense when a virus enters the body, alerting of an intruder and triggering an immune response in most mammals. But, according to a recent study published in

Researchers focused on pangolins because the exotic animal may have transmitted the virus to humans last year, creating the interspecies jump required for the current COVID-19 pandemic to take hold (bats have also been identified as possible agents of infection). To obtain their results, they analyzed the genome sequence of pangolins and compared it to other mammals including humans, cats, dogs, and cattle."Our work shows that pangolins have survived through millions of years of evolution without a type of antiviral defense that is used by all other mammals," says co-author Dr. Leopold Eckhart, of the Medical University of Vienna in Austria. "Further studies of pangolins will uncover how they manage to survive viral infections, and this might help to devise new treatment strategies for people with viral infections."In humans, coronavirus can cause an inflammatory immune response called a cytokine storm, which then worsens outcomes. Pharmaceutical suppression of gene signaling, the authors suggest, could be a possible treatment option for severe cases of COVID-19. Eckhart cautions though that such a remedy could open the door to secondary infections. "The main challenge is to reduce the response to the pathogen while maintaining sufficient control of the virus," he says. An overactivated immune system can be moderated, Eckhart says, "by reducing the intensity or by changing the timing of the defense reaction."While the study identified genetic differences between pangolins and other mammals, it did not investigate the impact of those differences on the antiviral response. Scientists don't yet understand how exactly pangolins survive coronavirus, only that their lack of these two signaling genes might have something to do with it. Eckhart adds that another gene, RIG-I, which also acts as a sensor against viruses, should be studied further as it could defend against coronaviruses. The study offers a starting point to better understand coronavirus's characteristics, the body's response, and the best options for treatment.

Microbes

May 6, 2020

https://www.sciencedaily.com/releases/2020/05/200506162205.htm

Scientists shed light on essential carbon-fixing machinery in bacteria

Scientists have been studying cyanobacteria and its many potential applications for decades, from cutting CO

New CU Boulder research published today in "This was a 50-year question, a long-standing thing that people could never tackle," said Jeffrey Cameron, an assistant professor in the Department of Biochemistry and coauthor of the new research.In his work as a postdoctoral researcher, Cameron figured out how carboxysomes are formed: from the inside out. But he couldn't determine their function in the cells because they struggled to grow under the microscope.He wanted to answer the questions of, how long do carboxysomes last? How long are they active? What happens to cells without carboxysomes?So, Cameron and his colleagues tracked specific enzymes within these cells' carboxysomes, by tagging them with a green fluorescent marker. They then added chemicals to curb the ability of the cell to make new carboxysomes. Researchers tracked them for several days using live cell imaging as they were passed from mother to daughter cells.Because the cells' ability to grow was dependent on their ability to fix carbon, in this way they could directly track the effect of the carboxysome on the cells' growth. The researchers found that by adjusting the amount of COAnd by filming thousands of cells and measuring all of them in the population, they uncovered several practical applications for engineering.About 5% of these carboxysomes were ultra-productive and could maintain their growth rate for over seven generations."This would be like having the same brain passed on from your great, great, great, great, great grandmother that's still functioning over that many generations," said Cameron. "If we could understand the principles of why these ones are so active, we might be able to significantly improve plant growth."There is now a huge push to try to put carboxysomes into plants to improve photosynthesis, which could greatly enhance plant yields, said Cameron, also of the Renewable and Sustainable Energy Institute (RASEI) at CU Boulder.Carboxysomes also have potential to serve as mini bioreactors, increasing the metabolism for the processes that create biofuels.Meantime, pathogenic bacteria, such as Salmonella, contain similar microcompartments that give them metabolic advantage in certain environments. Because humans do not have cyanobacteria or bacterial microcompartments, it may be possible to develop novel antibiotics that specifically target these bacterial structures, he added."I want to know, how can I elucidate the basic principles that will allow engineers to move forward?" said Cameron.

Microbes

May 6, 2020

https://www.sciencedaily.com/releases/2020/05/200506133608.htm

SMART researchers uncover new anti-phage defence mechanisms in bacteria

Researchers from Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore, have discovered a new anti-phage defence mechanism found in some bacteria, which uses previously unknown features to protect their DNA. The groundbreaking discovery enables scientists to overcome existing challenges in bacterial resistance to antibiotics. The growing antimicrobial resistance is a major concern for the global health community, and phage therapy is an important pillar in combating bacterial infections.

Bacteriophages, an effective alternative to fight bacteria that are resistant to commonly used antibiotics, work by injecting their own DNA into the bacteria where it can replicate to the point that it destroys the bacteria. In a paper titled "SspABCD-SspE is a phosphorothioation-sensing bacterial defence system with broad anti-phage activities" published in the journal Led by Professor Lianrong Wang at Wuhan University the paper was jointly written by a group of scientists at SMART's Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG), Shanghai Jiao Tong University, and Tsinghua University. SMART's AMR IRG is a translational research and entrepreneurship program that aims to solve the growing threat of resistance to antimicrobial drugs."We previously discovered a new type of defence mechanism that bacteria use against phages, where sulfur is inserted into the DNA backbone as a phosphorothioate modification on each strand of the DNA," says Professor Peter C Dedon, co-author of the paper and lead Principal Investigator at SMART AMR. "If the attacking phage DNA didn't have the modifications, host enzymes would chop the DNA into pieces to destroy it. This restriction-modification mechanism is like a bacterial immune system to protect against invaders.""What the team discovered now is an entirely new and different mechanism in which phosphorothioates are located on only one strand of DNA at very high-frequency. The host defence enzymes then nick one strand of the invader DNA to stop the virus from making copies of itself. Like a surgeon's knife compared to a meat cleaver."The newly identified SspABCD-SspE PT system is unique from the previously known PT modification system which uses multiple proteins and enzymes to attack phage DNA by chopping it into pieces. The discovery will help researchers understand how to tackle the ever-growing arsenal of bacterial defences against phages and can have huge implications for phage therapy."We keep pushing to discover DNA modification systems in phages as well as in bacteria. There are likely to be many more waiting to be found. We're finding some bizarre new ones that can be exploited to engineer phages to thwart bacterial defences in common pathogens," adds Professor Dedon, who is also a professor at Massachusetts Institute of Technology (MIT) and helped create the university's Department of Biological Engineering.

Microbes

May 6, 2020

https://www.sciencedaily.com/releases/2020/05/200506133607.htm

Dual personalities visualized for shape-shifting molecule

Australian and US researchers have made a breakthrough in understanding the structure of a key genetic molecule, called RNA, and revealing for the first time how these changes impact RNA's function.

Publishing in the journal RNA is a DNA-like molecule that encodes genetic information. Certain viruses -- including HIV and SARS-CoV2 -- use RNA as their genetic material. The team were able to apply the techniques they developed to reveal how the structure of HIV's RNA genome influences which proteins the virus produces.The international collaborative team was led by Walter and Eliza Hall Institute researcher Dr Vincent Corbin together with Mr Phil Tomezsko and Professor Silvi Rouskin at the Whitehead Institute for Biomedical Research, Boston (US). The research team also included the Institute's Computational Biology Theme Leader Professor Tony Papenfuss and mathematician and PhD student Mr Lachlan McIntosh.- A collaborative research team has used advanced computational methods to detect different structures of RNA, which until now could not be distinguished.- Using HIV as a model system, the team discovered that different structures of RNA influenced how the virus behaved. This is the first time changes in RNA structure have been shown to influence how this molecule controls cells' function.RNA is a molecule found in all living things that carries genetic information. RNA is an important regulator of how cells function, directly controlling which proteins are produced in cells, and can also switch genes on and off.RNA molecules have a two-dimensional structure which influences how the genetic information contained within them can be accessed, said Dr Corbin, who led the project's bioinformatics research."The big question in RNA biology has been whether RNA molecules have a single, constant structure, or whether they can shift between different structures -- and what this means for the function of a particular RNA molecule," he said."Our collaborators, led by Professor Silvi Rouskin, developed a technique for deciphering the structure of RNA molecules. We wanted to understand whether what we were detecting was a single structure of RNA, or an 'average' structure that blurs multiple different structures together."It's a bit like seeing red and yellow stripes, or blurring them together and thinking you can see orange," he said.By developing a computational algorithm, the team were able to detect and measure the amount of different RNA structures. "We could detect these both in a test tube and in living cells, so we next looked at whether these structures influenced how RNA functioned," Dr Corbin said.When RNA is produced in cells, it starts in a longer form that is 'spliced' or trimmed to remove unwanted parts."RNA splicing can influence how it encodes proteins," Dr Corbin said. "There are many examples of how altered RNA splicing influences how a cell functions -- and in some cases, changes in RNA splicing have been associated with cancer or neurodegenerative diseases."Certain viruses use RNA for their genome, including HIV and SARS-CoV2 (the coronavirus that causes COVID-19). In the case of HIV, RNA splicing influences which protein the virus produces -- which changes at different stages of the virus's lifecycle."Using the HIV genome as a model system, we looked at whether RNA structure influences how HIV's RNA is spliced. We discovered that RNA structure was a critical determinant of RNA splicing in HIV, and influenced which viral proteins were produced," Dr Corbin said."This is the first clear evidence of how RNA structure can control RNA function. The techniques we have developed have opened up a new field of research into the role of RNA structure in regulating the function of cells."Professor Papenfuss said the research showed how finely tuned biological systems are. "This study how very subtle changes in one tiny molecule can have big implications for the function of a virus. By using computational biology to unravel these changes, we've made a significant discovery about how viruses -- and potentially human cells -- function, which may underpin future discoveries about health and disease."The research was supported by the US National Institutes of Health, the Smith Family Foundation, the Burroughs Wellcome Fund, the Australian National Health and Medical Research Council and the Victorian Government.

Microbes

May 6, 2020

https://www.sciencedaily.com/releases/2020/05/200506133600.htm

New imaging method gives insights into how bacteria move and exchange genetic information

Scientists have made a pivotal breakthrough in advancing our understanding of how bacteria move and perform genetic exchange -- that could potentially lead to the development of new antimicrobial drugs.

A team of researchers from the University of Exeter's Living Systems Institute and the University of Frankfurt has made a crucial discovery around the structures of long filaments -- hair like appendages -- called type IV pili found on the surface of bacteria.Type IV pili are known to play an important role in how bacteria proliferate and form biofilms, through movement, genetic exchange, adhesion and communicating with other cells.Genetic exchange occurs when cells take up DNA -- the molecule that encodes an organisms' genetic code -- from their environment.DNA transfer plays a vital role in the bacteria's ability to become resistant to treatments. There are antibiotic resistance genes, for example, that get shared and thus render the treatment useless.In this new research, scientists have discovered that the bacterium Thermus thermophilus can produce two types of type IV pili -- one specialised for movement and one for genetic exchange.The pioneering research could allow scientists to target the two functions independently, for example by developing new drugs that stop bacteria from moving or becoming resistant to antibiotics.The study is published in leading journal Dr Vicki Gold, a Senior Lecturer at the University of Exeter and lead author of the paper said: "It will now be important to investigate if this phenomenon is a universal principle occurring in other bacteria expressing type IV pili. This would pave the way for the development of antimicrobials aimed to target a particular mechanism."Type IV pili are protrusions that are found across the surface of a bacterial cell, and are made up of thousands of copies of one protein.In the new study, the researchers used cryo-electron microscopy to determine structures of both type IV pili in unprecedented detail. The technique allowed the researchers to gather a vast array of detailed images of the structures in different orientations to create a detailed, 3D picture.The discovery that one of the pili is composed of a previously uncharacterised protein means that scientists are able to target the different functions to determine what is important for microbial proliferation and genetic exchange.As a result, they are able to conduct experiments to see how well bacteria proliferate, or take up DNA, when certain type of pilus formation are artificially impeded.Alexander Neuhaus, first author of the research and also from the University of Exeter said: "It is going to be interesting to discover how exactly the two pili fulfil their different functions and how bacteria control their production. Knowledge of these mechanisms could lead to new strategies for combatting bacterial infection."The research was carried out in collaboration with the laboratory of Prof. Beate Averhoff (University of Frankfurt) and is funded by the BBSRC.

Microbes

May 5, 2020

https://www.sciencedaily.com/releases/2020/05/200505190552.htm

Unraveling one of prion disease's deadly secrets

A molecular biologist at the University of Massachusetts Amherst who has for decades studied the nightmarish group of fatal diseases caused by prions -- chronic wasting disease in deer, mad cow in cattle and its human analog -- credits a middle-of-the-night dream for a crucial insight, a breakthrough she hopes could lead to a cure.

In a new paper in The infectious prion is an unusual pathogen, a protein without nucleic acid, she explains. Prion diseases were first described in the 1800s, and include scrapie in sheep and other neurodegenerative diseases such as mad cow disease and in humans, Creutzfeldt-Jakob disease, fatal familial insomnia and kuru from ritual cannibalism in Papua, New Guinea.Serio says, "These diseases are always fatal," but she and colleagues including first author Janice Villali work with natural yeast prions that can't be transmitted to humans or cause disease. "It's a good model system that is not infectious, and it grows really fast."It has been known for decades that prion protein (PrP) misfolding is a key part of the disease process, she adds. In these diseases, proteins fold into 3D shapes that cause disease. In mammals, the protein quality control system responds to folding mistakes with "chaperone" molecules that seek out misfolds and try to refold and correct mistakes.But prions misfold so quickly that chaperones can't keep up, Serio says. "That part was known," she adds, but scientists still could not figure out what was limiting the chaperone system, allowing prions to persist. "One key factor controlling the transition from harmless protein to invincible disease menace was so hidden and obscure that it had not been previously proposed," she says.Then, after a conference where she had talked intensely all day about prions, Serio had the crucial dream. "It came to me that the size of the aggregate nucleation seed mattered," she recalls. "So we went back and designed experiments to test the minimum size idea by mathematical modeling with co-first author Jason Dark, and it worked. That led to this investigation and why we're really excited about this paper."The first revelation was a surprise, Serio recalls -- prion aggregates come in different sizes. "Everybody knew of the nucleation seed, but no one knew they could be different sizes for the same protein." As prion proteins physically attach and the complex switches from one state to another, this minimum size is really important -- but why?It turns out, Serio says, that the seed complex must double in size for the disease to persist. It it starts with four molecules, it must reach eight. "This minimum size determines whether the chaperone can win. Four has to get to eight, but if you catch it early enough, if you pull out one side of the square, the amyloid structure can't double. Chaperones prevent the disease by preventing it from doubling in that first round."Another discovery is that if the minimum nucleation seed starting size is 10 and it must reach 20 to create two amyloids, that complex is an easier problem for chaperones to nip, Serio points out. "In yeast, the bigger the initial seed, the more difficult it is for the disease to resist chaperones and take hold because these protein quality controls have more time to act; the smaller seed is harder to cure because it doubles more quickly."She adds, "We realized that if we could control this transformation, we could stop the disease from arising, but we also realized that the same barrier would control going backwards and unfolding an established amyloid. The literature says that's a silly idea because prions survive and resist killing so well. But once we figured out this minimum size, we showed that it could also predict the frequency of prion curing under different growth conditions. Looking back, we can't figure out how we missed it."Serio says she and her team now know there are at least three nucleation sizes possible, and, "I suspect that it will turn out to be an infinite number," she adds. "In fact, we have shown that we can shift the nucleation size by changing the shape of the prion or by expressing a mutant form of the protein, opening the door to therapeutic intervention to reverse this process."

Microbes

May 5, 2020

https://www.sciencedaily.com/releases/2020/05/200505190550.htm

Mutations in SARS-CoV-2 offer insights into virus evolution

By analysing virus genomes from over 7,500 people infected with Covid-19, a UCL-led research team has characterised patterns of diversity of SARS-CoV-2 virus genome, offering clues to direct drugs and vaccine targets.

The study, led by the UCL Genetics Institute, identified close to 200 recurrent genetic mutations in the virus, highlighting how it may be adapting and evolving to its human hosts.Researchers found that a large proportion of the global genetic diversity of SARS-CoV-2 is found in all hardest-hit countries, suggesting extensive global transmission from early on in the epidemic and the absence of single 'Patient Zeroes' in most countries.The findings, published today in Co-lead author Professor Francois Balloux (UCL Genetics Institute) said: "All viruses naturally mutate. Mutations in themselves are not a bad thing and there is nothing to suggest SARS-CoV-2 is mutating faster or slower than expected. So far we cannot say whether SARS-CoV-2 is becoming more or less lethal and contagious."The small genetic changes, or mutations, identified were not evenly distributed across the virus genome. As some parts of the genome had very few mutations, the researchers say those invariant parts of the virus could be better targets for drug and vaccine development."A major challenge to defeating viruses is that a vaccine or drug might no longer be effective if the virus has mutated. If we focus our efforts on parts of the virus that are less likely to mutate, we have a better chance of developing drugs that will be effective in the long run," Professor Balloux explained."We need to develop drugs and vaccines that cannot be easily evaded by the virus."Co-lead author Dr Lucy van Dorp (UCL Genetics Institute) added: "There are still very few genetic differences or mutations between viruses. We found that some of these differences have occurred multiple times, independently of one another during the course of the pandemic -- we need to continue to monitor these as more genomes become available and conduct research to understand exactly what they do."The results add to a growing body of evidence that SARS-CoV-2 viruses share a common ancestor from late 2019, suggesting that this was when the virus jumped from a previous animal host, into people. This means it is most unlikely the virus causing Covid-19 was in human circulation for long before it was first detected.In many countries including the UK, the diversity of viruses sampled was almost as much as that seen across the whole world, meaning the virus entered the UK numerous times independently, rather than via any one index case.The research team have developed a new interactive, open-source online application so that researchers across the globe can also review the virus genomes and apply similar approaches to better understand its evolution.Dr van Dorp said: "Being able to analyse such an extraordinary number of virus genomes within the first few months of the pandemic could be invaluable to drug development efforts, and showcases how far genomic research has come even within the last decade. We are all benefiting from a tremendous effort by hundreds of researchers globally who have been sequencing virus genomes and making them available online."The study was conducted by researchers in the UCL Faculties of Life Sciences and Medical Sciences, alongside colleagues from Cirad and Université de la Réunion, University of Oxford, and Imperial College London, and supported by the Newton Fund UK-China NSFC initiative and the Biotechnology and Biological Sciences Research Council (BBSRC).

Microbes

May 5, 2020

https://www.sciencedaily.com/releases/2020/05/200505121648.htm

Coronavirus structure clue to high infection rate

Cornell University researchers studying the structure of the virus that causes COVID-19 have found a unique feature that could explain why it is so transmissible between people.

Researchers also note that, aside from primates, cats, ferrets and mink are the animal species apparently most susceptible to the human virus.Gary Whittaker, professor of virology, is the senior author on the study, which identifies a structural loop in the SARS-CoV-2 spike protein, the area of the virus that facilitates entry into a cell, and a sequence of four amino acids in this loop that is different from other known human coronaviruses in this viral lineage.An analysis of the lineage of SARS-CoV-2 showed it shared properties of the closely related SARS-CoV-1, which first appeared in humans in 2003 and is lethal but not highly contagious, and HCoV-HKU1, a highly transmissible but relatively benign human coronavirus. SARS-CoV-2 is both highly transmissible and lethal."It's got this strange combination of both properties," Whittaker said. "The prediction is that the loop is very important to transmissibility or stability, or both."Whittaker said the researchers are focused on further study of this structural loop and the sequence of four amino acids.Cats, ferrets and minks are also susceptible. In order to infect a cell, features of the spike protein must bind with a receptor on the host cell's surface, and cats have a receptor binding site that closely matches that of humans. To date, infections in cats appear to be mild and infrequent, and there is not evidence that cats can, in turn, infect humans.Whittaker added that investigations into feline coronaviruses could provide further clues into SARS-CoV-2 and coronaviruses in general.The study, Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop, was published in the For more information, see this Cornell Chronicle story:

Microbes

May 5, 2020

https://www.sciencedaily.com/releases/2020/05/200505121646.htm

Worms freeload on bacterial defence systems

Scientists have untangled a sensory circuit in worms that allows them to choose whether to spend energy on self-defence or rely on the help of nearby bacteria, a new study in

The paper describes a novel sensory circuit that, if also conserved in humans, could be used to switch on defence mechanisms and improve health and longevity.Bacteria, fungi, plants and animals all excrete hydrogen peroxide as a weapon. In defence, cells use enzymes called catalases to break down hydrogen peroxide into water and oxygen. But it is not known whether this mechanism is coordinated across different cells."We speculated that coordinating these hydrogen peroxide cell defences based on environmental cues would be beneficial because it would save the energetic cost of protection," explains lead author Jodie Schiffer, a graduate student at Northeastern University, Boston, US. "We used the worm Caenorhabditis elegans to study whether the brain plays a role in this coordination by collecting and integrating information from the environment."Schiffer and her team found 10 different classes of sensory neurons in the worms that could positively or negatively control peroxide resistance. Among them was a pair of neurons that sense taste and temperature and caused the largest increase in peroxide resistance, which the team decided to study further.To determine how the neurons transmit messages to tell the worm to change its peroxide defence mechanisms, the team set out to identify the hormones involved. They found that when the worms lacked a hormone called DAF-7, it doubled peroxide resistance. In a process of gene elimination, they established that the neurons release DAF-7, which in turn signals through a well-known communication pathway, via cells called interneurons, to coordinate with defence systems in the intestine. Together, these control the worm's peroxide resistance.As worms can be exposed to peroxides through food, and those with faulty DAF-7 hormones have feeding defects, the team next explored whether feeding directly affects peroxide defenses. They placed worms that had never been exposed to peroxides on plates of Escherichia coli (E. coli) bacteria -- their preferred snack -- and then measured peroxide resistance. They found that worms grown on plates with the most E. coli were most resistant to peroxides. By contrast, worms grown without E. coli for only two days had a six-fold drop in peroxide resistance. Worms with a mutation that slows down their eating also had lower peroxide resistance. Taken together, these results suggest that the presence of E. coli was important for peroxide resistance.To test this, they looked at whether the bacteria can protect worms from the lethal effects of peroxides. They exposed worms to high amounts of hydrogen peroxide that would normally kill them. In the presence of a mutant E. coli that cannot produce the hydrogen-peroxide-degrading catalase enzyme, the worms were killed, whereas in the presence of wild-type E. coli, they were protected."We have identified a sensory circuit in the worm's brain that helps them decide when it is appropriate to use their own defences and when it is best to freeload on the protection given by others in the environment," concludes senior author Javier Apfeld, Assistant Professor at Northeastern University. "Because sensory perception and catalases also determine health and longevity in other animals, it is possible that sensory modulation could be a promising approach for switching on defence systems that could improve health and increase lifespan."

Microbes

May 5, 2020

https://www.sciencedaily.com/releases/2020/05/200505110410.htm

Scientists observe bacteria tumble their way out of surface traps

While tracing the movement of

Bacteria can live as individuals, swimming freely around the environment, but eventually, they settle down on surfaces to form colonies and biofilms. To do so, bacteria randomly tumble to slow down and re-orientate themselves three-dimensionally, to explore and find the ideal environment."Tumbles are very interesting. The bacteria itself does not know where the environment is preferential for them," says first author Laurence Lemelle, a biophysicist at École Normale Supérieure de Lyon (Normal School of Lyon). "It doesn't know where to go, how to feel things. But it knows if the past environment was better or worse than the present." Bacteria use the gathered information to stop tumbling or lower the frequency of tumbling. "This means you swim more towards a direction. At the end, the population statistically swims towards the preferential conditions," she says.Some studies claim that bacteria don't tumble and only swim when they're near a surface. But Lemelle and her colleagues say that claim sounds unlikely. Physics predicts that bacteria would get trapped, running in infinite circles on the surface if they only swam.However, it's not easy to track these tiny creatures. Propelling forward with their several tails known as flagella, bacteria swim 20 times the length of their body in one second, and tumble happens even quicker, at one-tenth of a second. In fact, you're likely to miss the tumble even if your camera is high-res enough to film bacteria. To take a close look at how bacteria escaped from the surface, the team built a high-magnification, high-sensitivity, high-speed camera equipped with night vision.The recording showed that when the bacteria swim near the surface, the water friction on the body near the surface causes the trajectory to bend. To prevent being trapped running in circles on the surface, the bacteria tumbles. It decelerates, and one of the flagella jiggles out of place, reorienting where it was heading. In some cases, like swimmers pushing off a pool wall, the jiggling flagella kicks on the surface, resulting in a sharper turn. The wild flagellum then returns to the bundle, accelerates the bacteria, and goes back to swimming."We now know that bacteria can tumble on surfaces, and these tumbles are very specific," said Lemelle. "Elucidating the strategy of surface exploration that is underlined by these tumbles is an important future step."To the bacteria, tumbling allows them to escape from the surface, enabling them to colonize other places and optimize the exploration of the surface itself. Bacteria can swim on cell surfaces until they get in contact with a specific receptor to optimize infections. They can also swim to settle down on surfaces that are difficult to clean to form bacterial biofilms, which can be antibiotic-resistant."Before the pandemia, the COVID pandemic, it was difficult to convince people that we need to anticipate and develop alternative approaches to reduce the surface biocontamination," said Lemelle. "People were like, 'We have plenty of antibiotics. There's resistance, but we have time.' From a medical standpoint, understanding the near-surface tumbling events of bacteria can help limit the biocontamination of surfaces and develop antibacterial methods."

Microbes

May 5, 2020

https://www.sciencedaily.com/releases/2020/05/200505105317.htm

Protective shield: How pathogens withstand acidic environments in the body

Certain bacteria, including the dangerous nosocomial pathogen MRSA, can protect themselves from acidic conditions in our body and thus ensure their survival. Researchers at the Biozentrum of the University of Basel have now elucidated an important mechanism in this process. A transport protein involved in cell wall biosynthesis plays a key role, they report in the journal

Each year, thousands of patients in Swiss hospitals become infected with dangerous pathogens that can hardly be controlled with antibiotics. The methicillin-resistant bacterium Staphylococcus aureus, MRSA for short, is particularly feared among the multi-resistant nosocomial germs. It can cause severe wound, respiratory and urinary tract infections and life-threatening sepsis. This is aggravated by the fact that MRSA causes chronic infections.The bacterial cell wall is a key target in the search for new antimicrobials, as only an intact cell wall can protect the pathogens from the host's immune defence and from antibiotics. In a recent study, scientists led by Prof. Camilo Perez from the University of Basel's Biozentrum have elucidated the structure and function of a flippase transporter involved in the synthesis of lipoteichoic acids in the pathogen MRSA. Lipoteichoic acids are important biopolymers that provide stability to the cell wall of Gram-positive bacteria, facilitate colonization of the host and contribute to repelling antibiotics.The cell wall is a highly dynamic layer that surrounds the cell membrane and protects bacteria. Lipoteichoic acids are long-chain biopolymers that are embedded in the cell wall. However, they only remain in place because they are bound to an "anchor" molecule at the cell membrane. Without this "anchor," lipoteichoic acids are not able to provide stability to the cell wall. "Based on our structural and functional analyses, we have been able to show for the first time how the "anchor" arrives at its destination and how bacteria energize this process," explains Perez. By moving hydrogen ions across the cell membrane, the flippase transporter is flipping the "anchor" molecule from the inside of the bacterial membrane, the site of its synthesis, to the outside, the site of lipoteichoic acid production."The fact that the transport of hydrogen ions is coupled with the synthesis of lipoteichoic acid represents a major survival advantage for these bacteria," says Perez. "The niches in the human body, which are preferentially colonized by Staphylococcus aureus, usually have an acidic microclimate. This means that the concentration of hydrogen ions is higher in these niches. The bacteria withstand these acidic conditions by simply building up a thicker protective layer of lipoteichoic acids."The researchers have also been able to show that Staphylococcus aureus lacking the flippase transporter display severe growth defects upon acidic stress. According to the researchers, the flippase is essential for the survival of Staphylococcus aureus in our body and could be considered as a new pharmacological target for the treatment of dangerous MRSA infections.

Microbes

May 4, 2020

https://www.sciencedaily.com/releases/2020/05/200504114124.htm

Viruses from feces can help combat obesity and diabetes

Obese mice with unhealthy lifestyles gain significantly less weight and avoid type 2 diabetes when they receive viruses transplanted from the stool of lean mice. These are the findings of a new University of Copenhagen study.

In recent years, faecal transplants from healthy donors to sick patients have become a popular way of treating a serious type of diarrhea caused by the bacterium Clostridioides difficile in humans. Recent trials in mice suggest that a similar treatment, in which only the virus in stool is transplanted, may help people suffering from obesity and type 2 diabetes. The majority of virus particles transmitted are so-called bacteriophages -- viruses that specifically attack other bacteria and not humans."When we transmit virus particles from the faeces of lean mice to obese ones, the obese mice put on significantly less weight compared to those that do not receive transplanted faeces," says Professor with Special Responsibilities (MSO) and senior author of the study, Dennis Sandris Nielsen of the University of Copenhagen's Department of Food Science.The method also seems to protect the mice against developing glucose intolerance (a hall mark of type 2 diabetes), a disease that inhibits the body from properly absorbing sugar. The experiments demonstrated that the obese mice that received an intestinal virus transplant from lean mice reacted to a shot of glucose no differently than the lean ones."In the obese mice on high fat diet, that didn't receive the virus transplant, we observed decreased glucose tolerance, which is a precursor of diabetes. Thus, we have influenced the gut microbiome in such a way that the mice with unhealthy lifestyles do not develop some of the common diseases triggered by poor diet," explains PhD student Torben Sølbeck Rasmussen, first author of the study.He emphasizes that the method is not a stand-alone solution and that it must be complemented with a change in diet. Furthermore, the treatment will probably not be targeted at general obesity, but more towards the most serious cases.It is understood that obesity and type 2 diabetes are linked to imbalances in the gastrointestinal microbiome, also known as gut flora. In recent years, it has been discovered that the composition of viruses in the gut plays a crucial role in the balance of this microbiome."If one eats poorly for long enough, they risk creating an imbalance in their intestinal tract. Here, we have a means of recuperating balance by shooting missing virus particles back into the system," says Dennis Sandris Nielsen.The researchers extracted faeces from mice fed a standard low-fat diet over a period of time. The stool was then filtered so that all live bacteria were sorted out, while the virus particles -- mainly bacteriophages -- were concentrated. The viruses were transplanted via a tube into the mice that had been on high-fat diets for 6 weeks. The mice continued the fatty diet for another six weeks. Thereafter, the mice were examined after a glucose test and measured for weight gain.The study addresses one of the current problems with faecal transplants. Today, stool is transplanted in an unfiltered form, in the belief that it is the gut bacteria which are most effective. However, in rare cases, the method produces side effects when diseases are inadvertently transmitted via the transplanted stool bacteria. Indeed, a patient in the United States died from just such an occurrence last year."Our study demonstrates that there is an effect after the live bacteria have been filtered from stool. Therefore, primarily virus particles are transmitted. This makes the method safer," says Dennis Sandris Nielsen.He expects that it will be a number of years before the method can be broadly deployed. More experiments are needed, and obviously, human trials as well."Mice are the first step. But because the findings suggest that it will work in humans, that is the next. Our hope is that, in the long term, a well-defined cocktail of bacteriophages can be developed that has a minimal risk of side effects," concludes Dennis Sandris Nielsen.The results demonstrated significantly decreased weight gain in mice on a high-fat diet with transplanted intestinal viruses, compared against non-transplanted mice on the high-fat diet. At the same time, the blood glucose tolerance of transplanted mice was normalised, whereas it was reduced in the other obese mice.Faecal transplantation, also known as faecal microbiota transplant, is the transfer of gut bacteria from a healthy donor to a sick recipient. The method used in this study is known as Faecal Virome Transplantation. The method filters stool of live bacteria so that primarily virus particles are transmitted.Researchers do not yet know how long the effect of each transplant is. The study demonstrates an effect of at least 6 weeks.

Microbes

May 4, 2020

https://www.sciencedaily.com/releases/2020/05/200504101618.htm

Activation of the SARS coronavirus 2 revealed

The SARS coronavirus 2 (SARS-CoV-2) infects lung cells and is responsible for the COVID-19 pandemic. The viral spike protein mediates entry of the virus into host cells and harbors an unusual activation sequence. The Infection Biology Unit of the German Primate Center (DPZ) -- Leibniz Institute for Primate Research has now shown that this sequence is cleaved by the cellular enzyme furin and that the cleavage is important for the infection of lung cells. These results define new starting points for therapy and vaccine research. In addition, they provide information on how coronaviruses from animals need to change in order to be able to spread in the human population (

The new coronavirus SARS-CoV-2 has been transmitted from animals to humans and is spreading worldwide. It causes the new lung disease COVID-19, which has already killed over 200,000 people. The spike protein on the virus surface serves as a key for the virus to enter host cells. It facilitates viral attachment to cells and fuses the viral with a cellular membrane, thereby allowing the virus to deliver its genome into the cell, which is essential for viral replication. For this, activation sequences of the spike protein need to be cleaved by cellular enzymes, called proteases. The spike protein of SARS-CoV-2 carries an activation sequence at the so-called S1/S2 cleavage site, which is similar to those observed in highly pathogenic avian influenza viruses, but which has so far not been found in viruses closely related to SARS-CoV-2. The importance of this sequence for the virus was so far unknown.In their current study, the infection biologists of the German Primate Center led by Markus Hoffmann and Stefan Pöhlmann were able to show that the S1/S2 activation sequence of the SARS-CoV-2 spike protein is cleaved by the cellular protease furin and that this cleavage event is essential for the infection of lung cells. It is also important for the fusion of infected cells with non-infected cells, which might allow the virus to spread in the body without leaving the host cell."Our results suggest that inhibition of furin should block the spread of SARS-CoV-2 in the lung," says Stefan Pöhlmann, head of the Infection Biology Unit at DPZ. "Furthermore, our present study and previous work demonstrate that the virus uses a two-step activation mechanism: In infected cells, the spike protein has to be cleaved by the protease furin so that newly formed viruses can then use the protease TMPRSS2 for further cleavage of the spike protein, which is important for the entry into lung cells."For a live attenuated vaccine to trigger a strong immune response, it has to be able to replicate in the body to a limited extent, for example locally at the site of injection. "SARS-CoV-2 variants, in which the activation sequence for furin has been removed, could be used as a basis for the development of such live attenuated vaccines, since the lack of cleavage of the spike protein should greatly limit the spread of the virus in the body. A sufficiently attenuated virus would no longer be able to cause disease, but would still enable the immune system to react to the pathogen and, for example, produce neutralizing antibodies," says Markus Hoffmann, first author of the study.In wildlife, especially bats, a large number of coronaviruses that are closely related to SARS-CoV and SARS-CoV-2 has been discovered over the past 20 years. However, so far an S1/S2 activation sequence that can be cleaved by furin has only been detected in SARS-CoV-2. "Wildlife sampling and the targeted search for coronaviruses with a focus on the S1/S2 activation sequence is necessary to identify those viruses that have the potential to infect and efficiently spread in humans. In addition, in the case of potential future coronavirus outbreaks, we should specifically analyze the S1/S2 cleavage site as it might serve as a marker for human-to-human transmissibility," says Markus Hoffmann.

Microbes

May 1, 2020

https://www.sciencedaily.com/releases/2020/05/200501184314.htm

Window to another world: Life is bubbling up to seafloor with petroleum from deep below

The COVID-19 pandemic is a stark reminder that we move through a world shaped by unseen life. Bacteria, viruses, and other microscopic organisms regulate the Earth's vital functions and resources, from the air we breathe to all our food and most of our energy sources. An estimated one-third of the Earth's microbes are literally hidden, buried in sediments deep below the ocean floor. Now, scientists have shown that these "deep biosphere" microbes aren't staying put but are bubbling up to the ocean floor along with fluids from buried petroleum reservoirs. These hitchhikers in petroleum seeps are diversifying the microbial community that thrives at the seafloor, impacting deep-sea processes, such as carbon cycling, that have global implications.

"This study confirms that petroleum seeps are a conduit for transporting life from the deep biosphere to the seafloor," says co-author Emil Ruff, a scientist at the Marine Biological Laboratory (MBL), Woods Hole. The study, led by Anirban Chakraborty and Casey Hubert of the University of Calgary, is published this week in The team analyzed 172 seafloor sediment samples from the eastern Gulf of Mexico that had been collected as part of a 2011 survey for the oil industry. A fraction of these samples contained migrated gaseous hydrocarbons, the chief components of oil and gas. These petroleum seeps on the ocean floor harbored distinct microbial communities featuring bacteria and archaea that are well-known inhabitants of deep biosphere sediments."Whereas sedimentation slowly buries microbial communities into the deep biosphere, these results show that it's more of a two-way street. The microbes coming back up offer a window to life buried deeper below," Hubert says. "These relatively accessible surface sediments give us a glimpse into the vast, subsurface realm."The study also adds a new dimension to understanding the metabolic diversity of seabed petroleum seep microbial communities. "If it weren't for the microbes living at hydrocarbon seeps, the oceans would be full of gas and oil," Chakraborty says.Co-authors Bernie Bernard and James Brooks of TDI-Brooks International obtained the 172 Gulf of Mexico sediment cores and performed geochemical testing on them, setting the stage for microbiology testing at the University of Calgary."One of the strengths of this study is the large number of samples analyzed, allowing robust statistical inferences of the microbes present in the petroleum seeps," Ruff says. Because the seafloor is so difficult to access, explorations of deep-sea ecosystems are often limited by the number and quality of samples. The team used metagenomic approaches to determine what microbes were present in the sediment samples, and genome sequencing of particularly interesting organisms to indicate what their activity in the subsurface might be.

Microbes

May 1, 2020

https://www.sciencedaily.com/releases/2020/05/200501184106.htm

Infectious disease modeling study casts doubt on impact of Justinianic plague

Many have claimed the Justinianic Plague (c. 541-750 CE) killed half of the population of Roman Empire. Now, historical research and mathematical modeling challenge the death rate and severity of this first plague pandemic.

Researchers Lauren White, PhD and Lee Mordechai, PhD, of the University of Maryland's National Socio-Environmental Synthesis Center (SESYNC), examined the impacts of the Justinianic Plague with mathematical modeling. Using modern plague research as their basis, the two developed novel mathematical models to re-examine primary sources from the time of the Justinianic Plague outbreak. From the modeling, they found that it was unlikely that any transmission route of the plague would have had both the mortality rate and duration described in the primary sources. Their findings appear in a paper titled "Modeling the Justinianic Plague: Comparing hypothesized transmission routes" in "This is the first time, to our knowledge, that a robust mathematical modeling approach has been used to investigate the Justinianic Plague," said lead author Lauren White, PhD, a quantitative disease ecologist and postdoctoral fellow at SESYNC. "Given that there is very little quantitative information in the primary sources for the Justinianic Plague, this was an exciting opportunity to think creatively about how we could combine present-day knowledge of plague's etiology with descriptions from the historical texts."White and Mordechai focused their efforts on the city of Constantinople, capital of the Roman Empire, which had a comparatively well-described outbreak in 542 CE. Some primary sources claim plague killed up to 300,000 people in the city, which had a population of some 500,000 people at the time. Other sources suggest the plague killed half the empire's population. Until recently, many scholars accepted this image of mass death. By comparing bubonic, pneumonic, and combined transmission routes, the authors showed that no single transmission route precisely mimicked the outbreak dynamics described in these primary sources.Existing literature often assumes that the Justinianic Plague affected all areas of the Mediterranean in the same way. The new findings from this paper suggest that given the variation in ecological and social patterns across the region (e.g., climate, population density), it is unlikely that a plague outbreak would have impacted all corners of the diverse empire equally."Our results strongly suggest that the effects of the Justinianic Plague varied considerably between different urban areas in late antiquity," said co-author Lee Mordechai, an environmental historian and a postdoctoral fellow at SESYNC when he wrote the paper. He is now a senior lecturer at the Hebrew University of Jerusalem, and co-lead of Princeton's Climate Change and History Research Initiative (CCHRI). He said, "This paper is part of a series of publications in recent years that casts doubt on the traditional interpretation of plague using new methodologies. It's an exciting time to do this kind of interdisciplinary research!"Using an approach called global sensitivity analysis, White and Mordechai were able to explore the importance of any given model parameter in dictating simulated disease outcomes. They found that several understudied parameters are also very important in determining model results. White explained, "One example was the transmission rate from fleas to humans. Although the analysis described this as an important parameter, there hasn't been enough research to validate a plausible range for that parameter."These high importance variables with minimal information also point to future directions for empirical data collection. "Working with mathematical models of disease was an insightful process for me as a historian," reflected Mordechai. "It allowed us to examine traditional historical arguments with a powerful new lens."Together, with other recent work from Mordechai, this study is another call to examine the primary sources and narratives surrounding the Justinianic Plague more critically.

Microbes

May 1, 2020

https://www.sciencedaily.com/releases/2020/05/200501092909.htm

Exploiting a chink in the armor of bacteria could result in new drug therapies

Scientists have identified a key process in the way bacteria protect themselves from attack -- and it heralds a new strategy in the hunt for antibiotics.

The researchers from the University of Leeds have pieced together how bacteria build their outer, defensive wall -- in essence, the cell's armour plating.The research has focused on the gram-negative bacteria The findings are published today (01/05) in the journal Dr Antonio Calabrese, University Academic Fellow in the Astbury Centre for Structural Molecular Biology, led the research. He said: "Our findings are changing the way we think about the way these cells constantly renew and replenish the proteins that make up the outer membrane."Understanding that process of how bacteria build their cell wall in greater detail may identify ways we could intervene and disrupt it."In doing so, we can either destroy the bacteria altogether or reduce the rate at which they divide and grow, making bacterial infections less severe."We are at the start of a quest that could result in new, drug-based therapies that work either alone or with existing antibiotics to target these disease-causing bacteria."The research has focused on the role of a protein called SurA. Known as a chaperone, the job of SurA is to martial other proteins from where they are made, at the centre of the cell, to where they are needed, in this case to bolster the bacterium's outer wall.Proteins are long chains of amino acids that must adopt a defined structural shape in order to function effectively. Without the chaperone SurA, the essential proteins needed to build the cell wall run the risk of losing their structural integrity on their journey to the outer membrane.Using advanced analytical techniques, the scientists mapped how the chaperone SurA recognises proteins to transport them to the bacterial outer membrane.Dr Calabrese said: "For the first time we have been able to see the mechanism by which the chaperone, SurA, helps to transport proteins to the bacterial outer membrane. In effect it does this by cradling the proteins, to ensure their safe passage. Without SurA, the delivery pipeline is broken and the wall cannot be built correctly."Professor Sheena Radford, FRS, Director of the Astbury Centre for Structural Molecular Biology said "This is an exciting discovery in our quest to find weak spots in a bacteria's armoury that we can target to stop bacterial growth in its tracks and build much-needed new antibiotics."It's early days, but we now know how SurA works and how it binds its protein clients. The next step will be to develop molecules that interrupt this process, which can be used to destroy pathogenic bacteria."Dr David Brockwell, Associate Professor in the Astbury Centre for Structural Molecular Biology, said: "It was only through the work of a great team from across the Astbury Centre that we were able to finally understand how SurA shuttles proteins to the bacterial outer membrane."The research was funded by the UK Biotechnology and Biological Sciences Research Council and used equipment funded by the BBSRC and Wellcome Trust.

Microbes

April 30, 2020

https://www.sciencedaily.com/releases/2020/04/200430150224.htm

Better understanding of nature's nanomachines may help in design of future drugs

Many of the drugs and medicines that we rely on today are natural products taken from microbes like bacteria and fungi. Within these microbes, the drugs are made by tiny natural machines -- mega-enzymes known as nonribosomal peptide synthetases (NRPSs). A research team led by McGill University has gained a better understanding of the structures of NRPSs and the processes by which they work. This improved understanding of NRPSs could potentially allow bacteria and fungi to be leveraged for the production of desired new compounds and lead to the creation of new potent antibiotics, immunosuppressants and other modern drugs.

"NRPSs are really fantastic enzymes that take small molecules like amino acids or other similar sized building blocks and assemble them into natural, biologically active, potent compounds, many of which are drugs," said Martin Schmeing, Associate Professor in the Department of Biochemistry at McGill University, and corresponding author on the article that was recently published in In their paper featured on the cover of the May 2020 issue of "Scientists have long been excited about the potential of bioengineering NRPSs by identifying the order of building blocks and reorganizing the workstations in the enzyme to create new drugs, but the effort has rarely been successful," said Schmeing. "This is the first time anyone has seen how these enzymes transform keto acids into a building block that can be put into a peptide drug. This helps us understand how the NRPSs can use so very many building blocks to make the many different compounds and therapeutics."

Microbes

April 30, 2020

https://www.sciencedaily.com/releases/2020/04/200430150217.htm

Cracking the Lyme disease code

The next time a tick feeds on you, Washington State University researchers hope to make sure persistent arthritis caused by Lyme disease doesn't linger for a lifetime.

Troy Bankhead, associate professor in WSU's Veterinary Microbiology and Pathology department, and his team have spent more than a decade analyzing an immune evasive protein of Borrelia burgdorferi, the bacterium that causes tick-borne Lyme disease.With the lab's latest finding, that work is beginning to pay off.According to research recently published in "This really has a significant impact in the development of vaccines," Bankhead said. "If we can determine which proteins are shielded as opposed to which ones are not, then of course those that are not protected are going to be better candidates for a vaccine."The Centers for Disease Control and Prevention estimates some 300,000 people may get Lyme disease each year in the United States alone. It is most prevalent in the northeast.If not treated early with antibiotics, Lyme disease can cause lifelong arthritis, and in more severe cases, bladder infections, heart inflammation, and neurologic and cognitive issues like loss of memory and balance."We chose the arthritis-related protein because arthritis is the most common symptom you see in North America," Lone said.By engineering a strain of Borrelia burgdorferi in the lab without the surface lipoprotein VlsE, they were able to confirm it was protecting the arthritis-related protein from an antibody response.Bankhead and Lone tested the new Borrelia strain in mice and found the animals were more easily able to clear the infection.Then, Bankhead and Lone confirmed that the new Borrelia strain was susceptible to antibodies under the microscope.By using fluorescence microscopy, a process that uses energy from electrons to emit light under a microscope, Bankhead and Lone watched as antibodies were unable to bind to the protein responsible for Lyme's persistent arthritis when the VlsE protein was present.When the VlsE protein was removed, antibodies were able to recognize and bind to the arthritis-related protein. "When you don't have VlsE those bacteria light up and that is because those antibodies are able to bind and recognize that arthritis-related protein in the absence of that VlsE shield," Bankhead said. "That's exactly what we were seeing."Understanding the VlsE protein is acting as a shield for the bacterium's arthritic-causing protein is significant for vaccine development and future research. While it is unknown if other surface proteins are protected, Bankhead said it is likely. He noted the scientific community is gaining ground on understanding these proteins but producing any vaccine is well into the future.Still, the finding creates two avenues for researchers to eliminate Lyme disease: take down the VlsE shield, or, find a way for the antibody response to get in front of the ever-adapting bacterium and eliminate it."HIV/AIDS persists for years in human beings. The same thing happens with Borrelia, it persists," Lone said. "While this finding tells us a lot about Borrelia. Our next step is to understand how it persists. Once we understand the mechanism of persistence, we can eliminate the disease."

Microbes

April 30, 2020

https://www.sciencedaily.com/releases/2020/04/200430150202.htm

Scientists identify a new potential reservoir of latent HIV

Scientists have long known that even in the face of antiretroviral therapy, some HIV virus remains in infected individuals forever, hiding in small reservoirs of cells of the immune system. When these individuals discontinue the therapy, the virus almost always rebounds rapidly from the reservoirs, causing deadly symptoms to re-emerge.

These reservoirs remain the main obstacle to curing HIV/AIDS. But there is at present no easy way of targeting reservoir cells for elimination. Nor can scientists efficiently extract reservoir cells from patients to study them, and, ultimately, find ways to control them.The reason is that the virus in these cells is silent. As a result, the cells do not carry on their surfaces the viral proteins that would make them easy to find.Scientists have therefore been looking for other means to pinpoint reservoir cells.In a recent paper in "Our findings suggest that CD127 cells from tissues may be an important population to target for an HIV cure," says Roan, who is also an associate professor of urology at UC San Francisco.In addition, scientists can potentially use the CD127 protein as a handle to isolate reservoir cells from patients, and study what makes them able to silence the virus, and occasionally reactivate it.HIV targets immune cells, known as T cells, that reside primarily in lymphoid tissues, such as lymph nodes and tonsils. Yet HIV infection studies have largely focused on T cells circulating in the blood, which are relatively easy to gain access to -- volunteers are more likely to submit to a blood draw than a tissue biopsy.But focusing on T cells present in the blood is probably giving scientists a skewed view of the reservoir composition."We have long suspected that reservoir cells come in different flavors, and that different tissues harbor different types of reservoir cells. But that has been difficult to show because reservoir cells in infected individuals are rare. The vast majority of in vitro models of latency use cell lines or cells circulating in the blood," says Roan.Roan and her team, by contrast, have been studying HIV infection using tissue specimens. In previous work, her team exposed tonsil cells to HIV in the lab to see which ones were most susceptible to infection. Using a variety of experimental approaches, the team found that tonsil cells with the surface protein CD127 efficiently took up the HIV virus but only rarely let it replicate. By contrast, another type of tonsil cells, carrying CD57 on their surface, readily supported a productive infection.That was intriguing, but that did not necessarily mean that CD127 were reservoir cells."After HIV enters a cell, the cell still has ways to escape infection," says Feng Hsiao, a former research associate in Roan's lab and co-first author of the present study.One way is to prevent the virus from copying its genome. Unlike the genome of human cells, the HIV genome is made of RNA. One of the virus's first tasks upon entering a cell is to make DNA copies of its RNA genome, using a viral enzyme called reverse transcriptase.Cells can hamper this step by activating an enzyme called SAMHD1 that depletes the stores of building blocks the virus needs to copy its genome. There was some evidence that this mechanism might be at play in blood cells.However, in their present work, Roan and her team found that eliminating SAMHD1 by genetic manipulation did not allow CD127 cells to churn out virus, even though it boosted viral production by CD57 cells."This suggested to us that CD127 cells blocked the virus at a later step in its life cycle," says Julie Frouard, PhD, a postdoctoral scholar in Roan's lab and the other first-author of the study.The next step for the virus is to integrate a copy of its genome into the host cell's DNA. Once there, the viral genes can take advantage of the cell machinery to produce their own proteins, which assemble new viral particles that can go infect other cells.Reservoir cells harbor HIV's genetic material integrated in their own genomes, though they somehow silence it. The occasional mobilization of this material permits the release of infectious virus. Did CD127 tonsil cells allow HIV genome integration?To answer this question, the scientists extracted the genome of CD127 and CD57 cells that had been exposed to virus in the lab. Using genetic tools that can specifically detect integrated viral DNA sequences, they found that both cell types harbored copies of the virus's genome, even though CD127 cells produced far less virus than CD57 cells did. The CD127 cells appeared to favor a latent infection.And yet, the virus integrated in CD127 cells is not silenced forever. Roan and her team found that by treating latently infected CD127 cells with agents known to stimulate T cells, they could coax the cells to reactivate the virus.Hence, CD127 tissue cells could very well serve as reservoir cells in the body, keeping the virus dormant most of the time, yet able to occasionally activate it and release the seeds of a new round of infection."The ability of a specific type of tissue T cell to preferentially support latent infection is very intriguing, and can teach us much about how the tissue reservoir becomes established initially," says Roan.To what extent CD127 cells are a major component of the reservoir in people living with HIV awaits follow-up studies analyzing these cells from multiple tissue sites. Preliminary studies from Roan's team are encouraging, as they show that the CD127 marker on the cells' surface can indeed be used to purify enough infected tissue cells from infected individuals to allow further analyses.Meanwhile, "CD127 tonsil cells exposed to HIV in vitro provide a novel model to study viral latency in tissues," says Roan.Roan and her team have already started analyzing what makes CD127 cells uniquely prone to silent infections. By comparing all the genes expressed in CD127 and CD57 tonsil cells, they found evidence that CD127 cells are in a quiescent state that may prevent the expression of the virus's genes. Moreover, they also found that the virus's gene products, or RNAs, failed to undergo the necessary processing that would allow them to make viral proteins."Ultimately, our hope is that the mechanisms we uncover can be harnessed to control the latent reservoir and move us closer to achieving a cure for HIV," says Roan.

Microbes

May 1, 2020

https://www.sciencedaily.com/releases/2020/05/200501184301.htm

Antibodies from llamas could help in fight against COVID-19, study suggests

The hunt for an effective treatment for COVID-19 has led one team of researchers to find an improbable ally for their work: a llama named Winter. The team -- from The University of Texas at Austin, the National Institutes of Health and Ghent University in Belgium -- reports their findings about a potential avenue for a coronavirus treatment involving llamas on May 5 in the journal

The researchers linked two copies of a special kind of antibody produced by llamas to create a new antibody that binds tightly to a key protein on the coronavirus that causes COVID-19. This protein, called the spike protein, allows the virus to break into host cells. Initial tests indicate that the antibody blocks viruses that display this spike protein from infecting cells in culture."This is one of the first antibodies known to neutralize SARS-CoV-2," said Jason McLellan, associate professor of molecular biosciences at UT Austin and co-senior author, referring to the virus that causes COVID-19.The team is now preparing to conduct preclinical studies in animals such as hamsters or nonhuman primates, with the hopes of next testing in humans. The goal is to develop a treatment that would help people soon after infection with the virus."Vaccines have to be given a month or two before infection to provide protection," McLellan said. "With antibody therapies, you're directly giving somebody the protective antibodies and so, immediately after treatment, they should be protected. The antibodies could also be used to treat somebody who is already sick to lessen the severity of the disease."This would be especially helpful for vulnerable groups such as elderly people, who mount a modest response to vaccines, which means that their protection may be incomplete. Health care workers and other people at increased risk of exposure to the virus can also benefit from immediate protection.When llamas' immune systems detect foreign invaders such as bacteria and viruses, these animals (and other camelids such as alpacas) produce two types of antibodies: one that is similar to human antibodies and another that's only about a quarter of the size. These smaller ones, called single-domain antibodies or nanobodies, can be nebulized and used in an inhaler."That makes them potentially really interesting as a drug for a respiratory pathogen because you're delivering it right to the site of infection," said Daniel Wrapp, a graduate student in McLellan's lab and co-first author of the paper.Winter, the llama, is 4 years old and still living on a farm in the Belgian countryside along with approximately 130 other llamas and alpacas. Her part in the experiment happened in 2016 when she was about 9 months old and the researchers were studying two earlier coronaviruses: SARS-CoV-1 and MERS-CoV. In a process similar to humans getting shots to immunize them against a virus, she was injected with stabilized spike proteins from those viruses over the course of about six weeks.Next, researchers collected a blood sample and isolated antibodies that bound to each version of the spike protein. One showed real promise in stopping a virus that displays spike proteins from SARS-CoV-1 from infecting cells in culture."That was exciting to me because I'd been working on this for years," Wrapp said. "But there wasn't a big need for a coronavirus treatment then. This was just basic research. Now, this can potentially have some translational implications, too."The team engineered the new antibody that shows promise for treating the current SARS-CoV-2 by linking two copies of the llama antibody that worked against the earlier SARS virus. They demonstrated that the new antibody neutralizes viruses displaying spike proteins from SARS-CoV-2 in cell cultures. The scientists were able to complete this research and publish it in a top journal in a matter of weeks thanks to the years of work they'd already done on related coronaviruses.McLellan also led the team that first mapped the spike protein of SARS-CoV-2, a critical step toward a vaccine. (Wrapp also co-authored that paper along with other authors on the current This work was supported by the National Institute of Allergy and Infectious Diseases (U.S.), VIB, The Research Foundation-Flanders (Belgium), Flanders Innovation and Entrepreneurship (Belgium) and the Federal Ministry of Education and Research (Germany).The first antibodies the team identified in the initial SARS-CoV-1 and MERS-CoV tests included one called VHH-72, which bound tightly to spike proteins on SARS-CoV-1. In so doing, it prevented a pseudotyped virus -- a virus that can't make people sick and has been genetically engineered to display copies of the SARS-CoV-1 spike protein on its surface -- from infecting cells.When SARS-CoV-2 emerged and triggered the COVID-19 pandemic, the team wondered whether the antibody they discovered for SARS-CoV-1 would also be effective against its viral cousin. They discovered that it did bind to SARS-CoV-2's spike protein too, albeit weakly. The engineering they did to make it bind more effectively involved linking two copies of VHH-72, which they then showed neutralizes a pseudotyped virus sporting spike proteins from SARS-CoV-2. This is the first known antibody that neutralizes both SARS-CoV-1 and SARS-CoV-2.Four years ago, De Vlieger was developing antivirals against influenza A when Bert Schepens and Xavier Saelens asked whether she would be interested in helping to isolate antibodies against coronaviruses from llamas."I thought this would be a small side project," she said. "Now the scientific impact of this project became bigger than I could ever expect. It's amazing how unpredictable viruses can be."The paper's other authors are Gretel M. Torres, Wander Van Breedam, Kenny Roose, Loes van Schie, Markus Hoffmann, Stefan Pöhlmann, Barney S. Graham and Nico Callewaert.

Microbes

April 29, 2020

https://www.sciencedaily.com/releases/2020/04/200429144921.htm

Simulated deep-sea mining affects ecosystem functions at the seafloor

Polymetallic nodules and crusts cover many thousands of square kilometres of the world's deep-sea floor. They contain mainly manganese and iron, but also the valuable metals nickel, cobalt and copper as well as some of the high-tech metals of the rare earths. Since these resources could become scarce on land in the future -- for example, due to future needs for batteries, electromobility and digital technologies -- marine deposits are economically very interesting. To date, there is no market-ready technology for deep-sea mining. However, it is already clear that interventions in the seabed have a massive and lasting impact on the affected areas. Studies have shown that many sessile inhabitants of the surface of the seafloor depend on the nodules as a substrate, and are still absent decades after a disturbance in the ecosystem. Also, effects on animals living in the seabed have been proven. As part of the BMBF-funded project "MiningImpact," the Max Planck Institute in Bremen has now taken a closer look at the smallest seabed inhabitants and their performance.

The present study shows that microorganisms inhabiting the seafloor would also be massively affected by deep-sea mining. The team led by Antje Boetius, group leader at the Max Planck Institute for Marine Microbiology and director at the Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research, travelled to the so-called DISCOL area in the tropical East Pacific, about 3000 kilometres off the coast of Peru, to investigate conditions of the seafloor as well as the activity of its microorganisms. Back in 1989, German researchers had simulated mining-related disturbances at this site by ploughing the seabed in a manganese nodule area of three and a half kilometres in diameter with a plough-harrow, 4000 metres under the surface of the ocean."Even 26 years after this disturbance, the plough tracks on the seabed were still clearly visible," reports first author Tobias Vonnahme, who participated in the study as part of his diploma thesis. "And the bacterial inhabitants were also clearly affected." Compared to undisturbed regions of the seafloor, only about two thirds of the bacteria lived in the old tracks, and only half of them in fresher plough tracks. The rates of various microbial processes were reduced by three quarters in comparison to undisturbed areas, even after a quarter of a century. "Our calculations have shown that it takes at least 50 years for the microbes to fully resume their normal function," says Vonnahme.So deep down and far away from the strong currents on the sea surface, it is not so surprising that even small-scale traces of the DISCOL experiment were still visible. "However, also the biogeochemical conditions had undergone lasting changes," stresses Antje Boetius. According to the researchers, this is mainly due to the fact that the plough destroys the upper, active sediment layer. It is ploughed under or stirred up and carried away by the currents. In these disturbed areas, the microbial inhabitants can only make limited use of the organic material that sinks to the seafloor from upper water layers. As a result, they lose one of their key functions for the ecosystem. Microbial communities and their functions could thus be suitable as early indicators of damage to deep-sea ecosystems caused by nodule mining -- and of the extent of their potential recovery.All mining technologies for manganese nodules currently being developed will lead to a massive disturbance of the seabed down to a depth of at least ten centimetres. This is comparable to the disturbance simulated here, but in completely different dimensions. Commercial deep-sea mining would affect hundreds to thousands of square kilometres of seabed per year, while all plough tracks in the DISCOL combined only covered a few square kilometres. The damage to be expected is correspondingly greater, and it would be correspondingly more difficult for the ecosystem to recover, the researchers stress."So far, only few studies have dealt with the disturbance of the biogeochemical function of deep-sea floors caused by mining," explains Boetius. "With the present study, we are contributing to the development of environmental standards for deep-sea mining and pointing out the limits of seabed recovery. Ecologically sustainable technologies should definitely avoid removing the densely populated and bioactive surface layer of the seabed."

Microbes

April 29, 2020

https://www.sciencedaily.com/releases/2020/04/200429144916.htm

Common ways to cook chicken at home may not ensure safety from pathogens

For home cooks, widespread techniques for judging doneness of chicken may not ensure that pathogens are reduced to safe levels. Solveig Langsrud of the Norwegian Institute of Food, Fisheries and Aquaculture Research and colleagues present these findings in the open-access journal

Chicken can harbor the bacterial pathogens Salmonella and Campylobacter. High temperatures can kill these microbes, but enough may survive to cause illness if meat is undercooked. Recommendations for monitoring doneness vary widely, and the prevalence and safety of methods commonly used by home cooks have been unclear.To help clarify consumers' chicken cooking practices, Lansgrud and colleagues surveyed 3,969 private households across five European countries (France, Norway, Portugal, Romania, and the U.K.) on their personal chicken cooking practices. They also interviewed and observed chicken cooking practices in 75 additional households in the same countries.The analysis indicated that checking the inner color of chicken meat is a popular way to judge doneness, used by half of households. Other common methods include examining meat texture or juice color. However, the researchers also conducted laboratory experiments to test various techniques for judging doneness, and these demonstrated that color and texture are not reliable indicators of safety on their own: for example, the inner color of chicken changes at a temperature too low to sufficiently inactivate pathogens.Food safety messages often recommend use of thermometers to judge doneness, but the researchers found that the surface of chicken meat may still harbor live pathogens after the inside is cooked sufficiently. Furthermore, thermometers are not widely used; only one of the 75 observed households employed one.These findings suggest a need for updated recommendations that guarantee safety while accounting for consumers' habits and desire to avoid overcooked chicken. For now, the researchers recommend focusing on the color and texture of the thickest part of the meat, as well as ensuring that all surfaces reach sufficient temperatures."Consumers are often advised to use a food thermometer or check that the juices run clear to make sure that the chicken is cooked safely -- we were surprised to find that these recommendations are not safe, not based on scientific evidence and rarely used by consumers," adds Dr Langsrud. "Primarily, consumers should check that all surfaces of the meat are cooked, as most bacteria are present on the surface. Secondly, they should check the core. When the core meat is fibrous and not glossy, it has reached a safe temperature."

Microbes

April 29, 2020

https://www.sciencedaily.com/releases/2020/04/200429133955.htm

To prevent antimicrobial resistance, vaccinate the world's kids

Childhood vaccination may be a powerful tool in the fight against antimicrobial resistance in low- and middle-income countries, finds a new analysis led by researchers University of California, Berkeley.

Around the world, overuse of antibiotics is driving the proliferation of bacterial "superbugs" that have evolved to survive antimicrobial exposure, making humans more vulnerable to diseases like sepsis, tuberculosis, malaria and pneumonia. Countries classified as low- and middle- income currently bear the brunt of the human and economic impacts of antimicrobial resistance.The new study found that immunization with two common vaccines -- the pneumococcal conjugate and rotavirus vaccines -- significantly reduces the rates of acute respiratory infections and diarrhea among small children in these settings. And, with fewer children getting sick or severely sick, fewer are receiving antibiotic treatment."Right now, almost all countries have developed or are in the process of developing national action plans to address the crisis that antibiotic resistance poses to their health systems, but there is very little evidence addressing which interventions are effective," said Joseph Lewnard, an assistant professor of epidemiology at UC Berkeley, and lead author of the paper. "By providing hard numbers on the substantial impact that has been achieved with just these two vaccines alone, our work demonstrates that vaccines should be among the interventions that are strongly prioritized."The study, which is the first to examine the connection between vaccination and antibiotic use in low- and middle-income settings, appears online April 29 in the journal Pneumococcal conjugate vaccines protect against the bacterium Using data from health and demographic studies of 78 low- and middle-income countries, the researchers found that pneumococcal and rotavirus vaccines prevent an estimated 19.7% of antibiotic-treated acute respiratory infections and 11.4% of antibiotic-treated episodes of diarrhea in children under five years old.By combining data on the effectiveness of the two vaccines with current vaccination rates, the team projected that the inoculations are now preventing 23.8 million and 13.6 million episodes of antibiotic-treated acute respiratory infections and diarrhea each year, respectively, among children under the age of five in these settings around the world.If universal vaccination was achieved, an additional 40 million cases of antibiotic-treated illness could be prevented each year, they predicted.These numbers are likely underestimates, Lewnard said."We're not accounting for the fact that there are indirect reductions in disease associated with declining transmission of the pathogens themselves, and that there might be additional benefits in other age groups as well," Lewnard said. "Moreover, we are looking at a narrow spectrum of all pneumococcal diseases, which, further, include ear infections and sinusitis cases that often receive antibiotic treatment."At this point, there isn't enough data on the effectiveness of other efforts to combat antibiotic resistance, such as improving hygiene and sanitation or reducing agricultural use of antibiotics, to know how they compare to vaccination, Lewnard said.While the two vaccines are commonly administered to children under 2 years old in high-income countries, children in low- and middle-income countries do not always receive them because of their relatively high cost and families' lower access to health care.Charities like GAVI, the Vaccine Alliance are working aggressively to expand access to vaccinations, especially in low-income settings. Lewnard said he hopes this study motivates countries that are not eligible for this type of aid, such as middle-income countries and low-income countries transitioning to middle-income status, to provide this support for their children."Effects on antibiotic use and antimicrobial resistance have not been included in economic assessments of the value of these vaccine programs," Lewnard said. "As low- and middle-income countries make decisions around maintaining or introducing these vaccination programs, it's very important to have evidence that demonstrates the impact these vaccines are having domestically."

Microbes

April 29, 2020

https://www.sciencedaily.com/releases/2020/04/200429111136.htm

New insight into bacterial structure to help fight against superbugs

Scientists from the University of Sheffield have produced the first high-resolution images of the structure of the cell wall of bacteria, in a study that could further understanding of antimicrobial resistance.

The research, published in The findings set a new framework for understanding how bacteria grow and how antibiotics work, overturning previous theories about the structure of the outer bacterial layers.The images give unprecedented insight into the composition of the bacterial cell wall and will inform new approaches to developing antibiotics in order to combat antibiotic resistance. There are no other examples of studies of the cell wall in any organism at comparable resolution, down to the molecular scale.Laia Pasquina Lemonche, a PhD Researcher from the University of Sheffield's Department of Physics and Astronomy, said: "Many antibiotics work by inhibiting the bacteria's production of a cell wall, a strong but permeable skin around the bacteria which is critical for its survival."We still don't understand how antibiotics like penicillin kill bacteria, but this isn't surprising because until now we had remarkably little information about the actual organisation of the bacterial cell wall. This study provides that essential stepping stone which we hope will lead to both a better understanding of how antibiotics work and to the future development of new approaches to combat antimicrobial resistance."The team used an advanced microscopy technique called Atomic Force Microscopy (AFM), which works by using a sharp needle to feel the shape of a surface and build an image similar to a contour map, but at the scale of individual molecules.Professor Jamie Hobbs, Professor of Physics at the University of Sheffield, said: "It is by physicists and biologists working together that we've been able to make these breakthroughs in our understanding of the bacterial cell wall."The researchers are now using the same techniques to understand how antibiotics change the architecture of the cell wall and also how changes in the cell wall are important in antimicrobial resistance.

Microbes

April 29, 2020

https://www.sciencedaily.com/releases/2020/04/200429105832.htm

Scientists explore links between genetics, gut microbiome and memory

A new study is among the first to trace the molecular connections between genetics, the gut microbiome and memory in a mouse model bred to resemble the diversity of the human population.

While tantalizing links between the gut microbiome and brain have previously been found, a team of researchers from two U.S. Department of Energy national laboratories found new evidence of tangible connections between the gut and the brain. The team identified lactate, a molecule produced by all species of one gut microbe, as a key memory-boosting molecular messenger. The work was published April 17 in the journal BMC Microbiome."Our study shows that the microbiome might partner with genetics to affect memory," said Janet Jansson, a microbial ecologist at Pacific Northwest National Laboratory and a corresponding author of the study.Scientists know that mice which have been fed microbes that benefit health, called probiotics, experience several positive benefits. Scientists also know that microbes produce molecules that travel through the blood and act as chemical messengers that influence other parts of the body, including the brain. However, it wasn't clear which specific microorganisms and microbial molecular messengers might influence memory until now."The challenge is that a mouse's unique genetic makeup and environmental conditions also impact its memory and microbiome," said Antoine Snijders, a bioscientist at Lawrence Berkeley National Laboratory (Berkeley Lab) and co-corresponding author. "To know if a microbial molecule influenced memory, we needed to understand the interaction between genetics and the microbiome."The microbiome's impact on memory is a very active research area now, he added, with more than 100 papers published in the last five years on links between common probiotics and memory.Before they could start hunting for molecules that might be involved with memory improvement, Jansson, Snijders and their colleagues needed to determine how genetics influence memory.The researchers started with a collection of mice called the Collaborative Cross. They bred 29 different strains of mice to mimic the genetic and physical diversity of a human population. It includes mice of different sizes, coat colors and disposition (e.g., timid or bold). Researchers also know the genome sequences of each strain.First, the team gave each strain of mice a memory test. Then they screened each strain for genetic variations and correlated these variations to the memory results. They found two sets of genes associated with memory. One was a set of new candidate genes for influencing cognition, while the other set of genes was already known.Next, the researchers analyzed the gut microbiome of each strain so they could make microbial connections to the genetics and memory links they already had. They identified four families of microbes that were associated with improved memory. The most common of those was a species of Lactobacillus, L. reuteri.To test this association, the researchers fed L. reuteri to germ-free mice without any gut microbes and then tested the mice's memory. They saw a significant improvement relative to germ-free mice not fed microbes. They also found the same improvement when they fed germ-free mice one of two other Lactobacillus species."While a link between Lactobacillus and memory was previously reported, we also found it independently in this unbiased genetic screen," Snijders said. "These results suggest that genetic variation in large part controls memory, as well as the differences in the composition of the gut microbiome across strains."Finally, the researchers wanted to identify which microbe-related molecules might be involved with memory enhancement. They analyzed stool, blood and brain tissue from germ-free mice each fed a specific species of Lactobacillus. Lactate was one of the common metabolic molecular byproducts; it is also a molecule that all Lactobacillus strains produce.The team fed lactate to mice previously identified to have poor memory and noticed that their memory improved. Mice fed lactate or Lactobacillus microbes also had increased levels of gamma-aminobutyric acid (GABA), a molecular messenger linked to memory formation in their brains.To see if the same molecular mechanism might apply in humans too, the researchers contacted Paul Wilmes, at the University of Luxembourg, who developed a tiny chip that mimics where microbes interact with human intestinal tissue. When Wilmes and his colleagues tested L. reuteri in this chip, they saw that lactate produced by the microbes traveled through the human gut tissue, indicating that it could enter the bloodstream and potentially travel to the brain."While this research strengthens the idea that diet, genetics, and behaviors -- like memory -- are connected, further work is needed to show if Lactobacillus can improve memory in humans," Jansson said.Snijders agreed, adding that it might be possible one day to use probiotics to improve memory in targeted populations, such as people with learning disabilities and neurodegenerative disorders.

Microbes

April 28, 2020

https://www.sciencedaily.com/releases/2020/04/200428112546.htm

Synthetic antibodies built with bacterial superglue could help fight emerging viruses

Synthetic antibodies constructed using bacterial superglue can neutralise potentially lethal viruses, according to a study published on April 21 in

The findings provide a new approach to preventing and treating infections of emerging viruses and could also potentially be used in therapeutics for other diseases.Bunyaviruses are mainly carried by insects, such as mosquitoes, and can have devastating effects on animal and human health. The World Health Organization has included several of these viruses on the Blueprint list of pathogens likely to cause epidemics in humans in the face of absent or insufficient countermeasures."After vaccines, antiviral and antibody therapies are considered the most effective tools to fight emerging life-threatening virus infections," explains author Paul Wichgers Schreur, a senior scientist of Wageningen Bioveterinary Research, The Netherlands. "Specific antibodies called VHHs have shown great promise in neutralising a respiratory virus of infants. We investigated if the same antibodies could be effective against emerging bunyaviruses."Antibodies naturally found in humans and most other animals are composed of four 'chains' -- two heavy and two light. VHHs are the antigen-binding domains of heavy chain-only antibodies found in camelids and are fully functional as a single domain. This makes VHHs smaller and able to bind to pathogens in ways that human antibodies cannot. Furthermore, the single chain nature makes them perfect building blocks for the construction of multifunctional complexes.In this study, the team immunised llamas with two prototypes of bunyaviruses, the Rift Valley fever virus (RVFV) and the Schmallenberg virus (SBV), to generate VHHs that target an important part of the virus' infective machinery, the glycoprotein head. They found that RVFV and SBV VHHs recognised different regions within the glycoprotein structure.When they tested whether the VHHs could neutralise the virus in a test tube, they found that single VHHs could not do the job. Combining two different VHHs had a slightly better neutralising effect against SBV, but this was not effective for RVFV. To address this, they used 'superglue' derived from bacteria to stick multiple VHHs together as a single antibody complex. The resulting VHH antibody complexes efficiently neutralised both viruses, but only if the VHHs in the complex targeted more than one region of the virus glycoprotein head.Studies in mice with the best performing VHH antibody complexes showed that these complexes were able to prevent death. The number of viruses in the blood of the treated mice was also substantially reduced compared with the untreated animals.To work in humans optimally, antibodies need to have all the effector functions of natural human antibodies. To this end, the team constructed llama-human chimeric antibodies. Administering a promising chimeric antibody to mice before infection prevented lethal disease in 80% of the animals, and treating them with the antibody after infection prevented mortality in 60%."We've harnessed the beneficial characteristics of VHHs in combination with bacterial superglues to develop highly potent virus neutralising complexes," concludes senior author Jeroen Kortekaas, Senior Scientist at Wageningen Bioveterinary Research, and Professor of the Laboratory of Virology, Wageningen University, The Netherlands. "Our approach could aid the development of therapeutics for bunyaviruses and other viral infections, as well as diseases including cancer."

Microbes

April 28, 2020

https://www.sciencedaily.com/releases/2020/04/200428112540.htm

Immune-regulating drug improves gum disease in mice

A drug that has life-extending effects on mice also reverses age-related dental problems in the animals, according to a new study published today in

Periodontal disease, also known as gum disease, is a common problem in older adults that causes painful inflammation, bone loss and changes in the good bacteria that live in the mouth. Yet there are no treatments available beyond tooth removal and/or having good oral hygiene. The findings suggest that treatments targeting the aging process in the mouth might help.Rapamycin is an immune-suppressing drug currently used to prevent organ rejection in transplant recipients. Previous studies in mice have also suggested that it may have life-extending effects, which has led to interest in studying the drug's effects in many age-related diseases."We hypothesised that biological aging contributes to periodontal disease, and that interventions that delay aging should also delay the progress of this disease," says lead author Jonathan An, Acting Assistant Professor at the Department of Oral Health Sciences, University of Washington, Seattle, US.To find out if rapamycin might slow periodontal disease, An and his colleagues added the drug to the food of middle-aged mice for eight weeks and compared their oral health with untreated mice of the same age. Similar to humans, mice also experience bone loss, inflammation and shifts in oral bacteria as they age.Using a 3D-imaging technique called micro-computed tomography, the team measured the periodontal bone, or bone around the tooth, of the rapamycin-treated and untreated mice. They showed that the treated mice had more bone than the untreated mice, and had actually grown new bone during the period they were receiving rapamycin.The work also showed that rapamycin-treated mice had less gum inflammation. Genetic sequencing of the bacteria in their mouths also revealed that the animals had fewer bacteria associated with gum disease and a mix of oral bacteria more similar to that found in healthy young mice."By targeting this aging process through rapamycin treatment, our work suggests that we can delay the progress of gum disease and actually reverse its clinical features," explains senior author Matt Kaeberlein, Professor of Pathology and Adjunct Professor of Oral Health Sciences at the University of Washington.However, Kaeberlein adds that while rapamycin is already used to treat certain conditions, it can make people more susceptible to infections and may increase their risk of developing diabetes, at least at the higher chronic doses typically taken by organ transplant patients. "Clinical trials in humans are needed to test whether rapamycin's potential oral health and other benefits outweigh its risks," he concludes.

Microbes

April 28, 2020

https://www.sciencedaily.com/releases/2020/04/200428112522.htm

Genomic secrets of scaly-foot snail from hydrothermal vents

Researchers have decoded for the first time the genome of Scaly-foot Snail, a rare snail inhabited in what scientists called 'the origin of life'- deep-sea hydrothermal vents characterized with near-impossible living conditions. Unraveling the genome of this unique creature will not only shed light on how life evolved billions of years ago, but will also lay the foundation for the discovery of potential remedies offered by these ancient creatures.

Despite an extreme environment characterized by high pressure, high temperature, strong acidity and low oxygen level which resembles living condition in pre-historic time, hydrothermal vents harbor a diverse amount of creatures -- most of which have huge potential for biomedical and other applications. Among other inhabitants of such difficult environment, Scaly-foot Snail, also known as "Sea Pangolin," is of particular interest to marine scientists.Scaly-foot Snail is the only extant gastropod (a major invertebrate animal, commonly known as snails and slugs,) alive that possesses armor-like scales -- an otherwise very common feature for gastropod during the Cambrian time over 540 million years ago. This snail is also the only organism in the world known to incorporate iron into its exoskeleton, and is also one of the top ten astounding marine species of the decade (2007-2017). Little is known, however, about its genome and unusual morphology, as the creature is extremely difficult to locate and collect.Now, a research team led by Prof. QIAN Peiyuan, Chair Professor of HKUST's Department of Ocean Science and Division of Life Science, managed to collect 20 scaly-foot snails at around 2,900 meters below sea level from the Indian Ocean in collaboration with researchers from the Japan Agency for Marine-Earth Science and Technology (JAMSTEC), and analyze the snail's genome sequence.Contrary to many scientists' expectation that the creature contains some new special genes that give rise to its bizarre morphology, the team actually discovered that all of the snail's genes already existed in other mollusks such as squid and pearl oyster, and the snail's gene sequence has remained almost unchanged throughout its evolution. The 25 transcription factors (a key protein that regulates many downstream gene expression levels) which contribute to the snail's scale and shell formation, as the team identified, have also contributed to the formation of many other unique hard-parts in Mollusca -- such as operculum in gastropods, beak in squid, spicule in chiton, or chaetae in polychaetes."Although no new gene was identified, our research offers valuable insight to the biomineralization -- a process where the clustering, positioning and on and off switching of a combination of genes defines the morphology of a species," Prof. Qian said. "Uncovering Scaly-foot Snail's genome advances our knowledge in the genetic mechanism of mollusks, laying the genetic groundwork which paves the way for application. One possible direction is how their iron-coated shells withstand heavy blows, which can provide us insights on ways to make a more protective armor."The findings were recently published in the scientific journal The study of genome sequencing of organisms often brings breakthrough to biomedical and other sectors. An enzyme of a microbe that lives in such vents -- for example, was recently used for the detection of COVID-19 as well as other viruses such as AIDS and SARS.

Microbes

April 28, 2020

https://www.sciencedaily.com/releases/2020/04/200428084707.htm

New DNA test will improve tracking of Salmonella food-poisoning outbreaks

Researchers report the development of a sensitive and specific assay to detect different serotypes of

Recent data from the Centers for Disease Control and Prevention (CDC) indicate that food poisoning caused by "The investigators developed an MCDA assay for each of the seven serovar (subtype)-specific targets of "The assays developed in this study are unique because the gene markers used were selected based on analyzing thousands of genomes. Thus, these markers future proof Traditional methods to distinguish Although there are hundreds of

Microbes

April 28, 2020

https://www.sciencedaily.com/releases/2020/04/200428093506.htm

They remember: Communities of microbes found to have working memory

Biologists studying collectives of bacteria, or "biofilms," have discovered that these so-called simple organisms feature a robust capacity for memory.

Working in the laboratory of University of California San Diego Professor Gürol Süel, Chih-Yu Yang, Maja Bialecka-Fornal and their colleagues found that bacterial cells stimulated with light remembered the exposure hours after the initial stimulus. The researchers were able to manipulate the process so that memory patterns emerged.The discovery reveals surprising parallels between low-level single-cell organisms and sophisticated neurons that process memory in the human brain."Even just a few years ago people didn't think bacterial cells and neurons were anything alike because they are such different cells," said Süel. "This finding in bacteria provides clues and a chance to understand some key features of the brain in a simpler system. If we understand how something as sophisticated as a neuron came to be -- its ancient roots -- we have a better chance of understanding how and why it works a certain way."The findings, described April 27 in the journal Following recent discoveries by the Süel lab that bacteria use ion channels to communicate with each other, new research suggested that bacteria might also have the ability to store information about their past states. In the new study, the researchers were able to encode complex memory patterns in bacterial biofilms with light-induced changes in the cell membrane potential of Bacillus subtilis bacteria. The optical imprints, they found, lasted for hours after the initial stimulus, leading to a direct, controllable single-cell resolution depiction of memory."When we perturbed these bacteria with light they remembered and responded differently from that point on," said Süel. "So for the first time we can directly visualize which cells have the memory. That's something we can't visualize in the human brain."The ability to encode memory in bacterial communities, the researchers say, could enable future biological computation through the imprinting of complex spatial memory patterns in biofilms."Bacteria are the dominant form of life on this planet," said Süel. "Being able to write memory into a bacterial system and do it in a complex way is one of the first requirements for being able to do computations using bacterial communities."Further, as the researchers note in the study: "It may thus be possible to imprint synthetic circuits in bacterial biofilms, by activating different kinds of computations in separate areas of the biofilm... Overall, our work is likely to inspire new membrane-potential-based approaches in synthetic biology and provide a bacterial paradigm for memory-capable biological systems."Authors of the study included: Chih-Yu Yang, Maja Bialecka-Fornal, Colleen Weatherwax (graduate student), Joseph Larkin, Arthur Prindle, Jintao Liu, Jordi Garcia-Ojalvo and Gürol Süel.The study was supported by the National Institute of General Medical Sciences (R01 GM121888), the Howard Hughes Medical Institute-Simons Foundation Faculty Scholars program, the Spanish Ministry of Science, Innovation and Universities and FEDER (PGC2018-101251-B-I00), Maria de Maeztu Programme for Units of Excellence in R\&D (CEX2018-000792-M) and the Generalitat de Catalunya (ICREA Academia programme).

Microbes

April 27, 2020

https://www.sciencedaily.com/releases/2020/04/200427184138.htm

Virus-infected honey bees more likely to gain entrance to healthy hives

Honey bees that guard hive entrances are twice as likely to allow in trespassers from other hives if the intruders are infected with the Israeli acute paralysis virus, a deadly pathogen of bees, researchers report.

Their new study, reported in the "The most important finding of our study is that IAPV infection increases the likelihood that infected bees are accepted by foreign colonies," said Adam Dolezal, a professor of entomology at the University of Illinois at Urbana-Champaign who led the new research. "Somehow, the infected bees are able to circumvent the guards of foreign colonies, which they shouldn't be able to do."Previous studies have shown that IAPV-infected honey bees are more likely than healthy bees to lose their way when returning home from foraging trips. In commercial beekeeping operations where hives are stacked much closer together than in the wild, the virus is even more likely to spread from one infected colony to nearby healthy ones.To capture the behavior of individual bees, researchers tagged each one with the equivalent of a QR code and continuously monitored their interactions. The scientists were able to simultaneously track the behaviors of as many as 900 bees.In previous work, study co-author U. of I. entomologist Gene Robinson and his colleagues developed this automated system to study bees engaged in trophallaxis, a process by which honey bees exchange regurgitated food and other liquids. They used this system to study how IAPV infection might affect the bees' trophallaxis social network."Honey bees use trophallaxis to share food with each other as well as hormones and other signaling molecules that can affect their physiology and behavior. They do it in pairs by touching their mouthparts and antennae, and each bee does this with hundreds of partners a day," said Robinson, who directs the Carl R. Woese Institute for Genomic Biology at Illinois. "Trophallaxis is essential to the spread of information and nutrition throughout the hive, but unfortunately, a behavior performed with such close social contact also allows viral infections to be transmitted through a hive."In the new study, the scientists saw that honey bees altered their behavior in response to infection in their own hives. IAPV-infected bees -- and bees that had had their immune systems stimulated to mimic infection -- engaged in less trophallaxis than their healthy counterparts did.The infected bees were just as mobile as the other bees, so their lower rates of trophallaxis were not the result of sluggishness from being sick, Dolezal said. The researchers believe this change in behavior is a general response to a health threat and not specific to IAPV infection, which is in line with previous research.When the scientists placed honey bee workers at the entrance of a foreign hive, however, the infected bees engaged in more trophallaxis with the guards, the researchers found. The guards were more likely to admit them than to let in healthy bees or bees whose immune systems had been stimulated. This response was specific to IAPV infection."Something about them must be different," Dolezal said.To test whether the IAPV-infected bees were giving off a different chemical odor than their healthy nest mates, the researchers analyzed the chemistry of the hydrocarbons that coat the bees' exoskeletons. They discovered distinct hydrocarbon profiles for healthy bees, IAPV-infected bees and immunostimulated bees."It seems that the virus is changing how the bees smell, and perhaps the infected bees also are behaving in a way that is meant to appease the guards by engaging more in trophallaxus," Dolezal said.The new findings suggest that IAPV is evolving in ways that enhance its ability to infect as many hosts as possible, Dolezal said."If you're a virus, it's much more valuable to get transmitted to a new family group, like traveling from one city to a new city," he said. "And so how do you get there? You increase the chances that the sick bees leaving colony A are more likely to get into colony B."

Microbes

April 27, 2020

https://www.sciencedaily.com/releases/2020/04/200427184134.htm

Making sense of the viral multiverse

In November of 2019 -- likely, even earlier -- a tiny entity measuring just a few hundred billionths of a meter in diameter began to tear apart human society on a global scale. Within a few months, the relentless voyager known as SARS-CoV-2 had made its way to every populated corner of the earth, leaving scientists and health authorities with too many questions and few answers.

Today, researchers are scrambling to understand where and how the novel coronavirus arose, what features account for the puzzling constellation of symptoms it can cause and how the wildfire of transmission may be brought under control. An important part of this quest will involve efforts to properly classify this emergent human pathogen and to understand how it relates to other viruses we may know more about.In a consensus statement, Arvind Varsani, a molecular virologist with ASU's Biodesign Center for Fundamental and Applied Microbiomics and a host of international collaborators propose a new classification system, capable of situating coronaviruses like SARS-CoV-2 within the enormous web of viruses across the planet, known as the virosphere.In order to adequately categorize this astonishing viral diversity, the group proposes a 15-rank classification scheme and describe how three human pathogens -- severe acute respiratory syndrome coronavirus (SARS CoV), Ebola virus, and herpes simplex virus 1, fit into the new framework.Varsani is joined by other elected executive members of the International Committee on Taxonomy of Viruses (ICTV), an all-volunteer organization of leading virologists from around the world, dedicated to designing a workable nomenclature for defining viral species. Within the ICTV, approximately 100 distinct working groups composed of specialists within all major viral families labor to bring order to the tangled skein of elements in the virosphere.The consensus statement appears in the advanced online edition of the journal The new ranking scheme, an elaboration of the earlier binomial classification system conceived by the great 18th century taxonomist Carl Linnaeus, seeks to incorporate the full range of genetic divergence in the virosphere.As a test case, the consensus statement shows how three human pathogens can be neatly incorporated into the new system. At the level of realm, the lowest and most inclusive in the new taxonomy, two RNA viruses, Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus (SARS-CoV) are grouped as 'riboviria', while herpes simplex 1, a double-stranded DNA virus, does not belong to the realm riboviria but is classified by five traditional ranks.Devising an inclusive viral taxonomy is of great practical importance. It can play a vital role in detecting and identifying the agents responsible for emergent epidemics in humans, livestock or plants. Establishing a virus' taxonomic status allows for clear and unambiguous communication among virologists and the broader scientific community."With viral metagenomic studies (which involve sequencing genetic material directly recovered from the environment), we are discovering large amounts of viruses that we can not really put into any particular order," Varsani says. "We were tasked with trying to come up with a better taxonomic framework." The new scheme relies in part on the conservation of key viral proteins and other properties found among taxonomically-related viruses for higher ranks.The virus causing the current outbreak of coronavirus disease, for example, has recently been named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), after the ICTV Coronaviridae Study Group determined the virus belongs to the existing species, "severe acute respiratory syndrome-related coronavirus," based in part on conserved proteins involved in SARS-CoV-2 viral replication. (Earlier classifications of coronaviruses were largely based on studies of serological reactivity with viral spike proteins, which give coronaviruses their characteristic mace-like appearance.)Even for scientists used to dealing in mind-bendingly extreme numbers, the virosphere is almost unfathomably vast. It has been estimated that 100 viruses could be assigned to every star in the entire universe without exhausting the world's supply, estimated at 1 nonillion (or 1 followed by 30 zeros)."One important thing about all these frameworks for viral taxonomy is that they're dynamic. As we discover more viruses, things will have to shift," Varsani says. "And the same thing has happened in the floral kingdom, where people once classified plants based on petals, leaves and other morphological features. And soon, as genetic information has come in, it has contradicted the prior classification that people had. These issues are common across plant, animal, fungal and bacterial classification and will certainly take a lot of convincing to the initial proposers of that taxonomy. Perhaps a crude example is the wrongful classification of a plant as a daisy in the Asteraceae family, but in fact it is a plant that is mimicking a daisy, because it wants a particular pollinator and is genetically not part of Asteraceae."But the extent and genetic diversity of the virome are just the beginning of the challenges facing researchers trying to develop a comprehensive taxonomy -- a mega taxonomy -- of the viral world. Viral lineages, for example, are exceptionally tricky to tease out. Unlike all cellular life on earth, viruses acquire their genomic material from many sources, a property known as polyphylogeny. Phenomena including horizontal transfer of genetic elements allow viruses to freely swap elements of their identity, leaving researchers without a clear line of descent.Further, viral mutation rates are much faster and more prolific than their cellular counterparts, owing to poor mechanisms of genomic proofreading and error correction, as well as selective pressures pushing their relentless diversification.Compared with other organisms, diversity among viruses is extreme. They may differ in their genetic material (RNA or DNA) and basic structure, (double or single stranded), as well as the orientation of their encoded genes. A further complication involves the fact that viral genomes may be distributed across distinct units, sometimes packaged together in a virion, or in separate virus particles, all of which are needed to infect a cell for replication to occur.While all eukaryotes share a last common ancestor, distinct from those of bacteria and archaea, allowing researchers to track their evolutionary origins and divergences many billions of years into the past, viruses lack a set of universally conserved genes needed to construct a proper phylogeny.The new 15-rank taxonomy elaborates on the Linnaean 7-tiered system of kingdom, phylum, class, order, family, genus, species. It also borrows physiological elements of the so-called Baltimore taxonomy, (developed by Nobel Laureate David Baltimore). The Baltimore system also recognizes 7 levels but is non-hierarchical and uses variables including genome type and replication-expression strategies to guide viral classification.The new taxonomy is a significant step forward in the quest to bring global organization to the viral world. Further, despite the extreme diversity of evolutionary histories present in polyphyletic viruses, a unity pointing to a primordial pool of virus-like genetic elements is beginning to emerge. The entire subsequent history of life on earth may be read as a ceaseless dynamic between these selfish agents and their cellular hosts.

Microbes

April 27, 2020

https://www.sciencedaily.com/releases/2020/04/200427140505.htm

Gut microbes influence how rat brains react to opioids

When Sierra Simpson was in college, she was sick for a year with recurring fevers and vomiting. Her doctors couldn't figure out what she had. Suspecting a bacterial infection, they tried treating her with high doses of antibiotics.

"It turned out I had malaria and needed a different treatment," Simpson said. "But by then the antibiotics had messed with my stomach and I felt more anxious than I had before."Antibiotics kill disease-causing bacteria, but they also destroy many of the beneficial bacteria living in our guts, a side effect that has been linked to a number of long-term health issues. That experience was the impetus for Simpson's interest in microbiome science and the gut-brain axis -- studies of the many ways that bacteria, viruses and other microbes living in our bodies influence our physical and mental well-being.As a now-healthy graduate student, Simpson first worked on techniques to visualize molecules in the brain. But she couldn't shake her interest in the gut microbiome and its connections to the brain."So one day, Sierra just walks into my lab and asks me if I'd be interested in exploring potential connections between the gut microbiome and what my lab typically studies -- drug abuse and addiction," said Olivier George, PhD, associate professor of psychiatry at University of California San Diego School of Medicine. "I was reluctant at first. After all, I figured if there was something there, someone would've discovered it by now. But we decided to give it a try."In a study published April 27, 2020 in "Like you often have to do in science, we first hit the problem with a hammer to see how the system breaks, then backtrack from there," Simpson said.By that she means that in order to determine if the gut microbiome influenced drug addiction, they first needed to compare an organism with a normal gut microbiome to one without. To do that, the researchers gave some rats antibiotics that depleted 80 percent of their gut microbes. All of the rats -- those with and without gut microbes -- were dependent on the prescription opioid pain reliever oxycodone. Then some of the rats from each group went into withdrawal."To me, the most surprising thing was that the rats all seemed the same on the surface," George said. "There weren't any major changes in the pain-relieving effect of opioids, or symptoms of withdrawal or other behavior between the rats with and without gut microbes."It wasn't until the team looked at the rats' brains that they saw a significant difference. The typical pattern of neuron recruitment to different parts of the brain during intoxication and withdrawal was disrupted in rats that had been treated with antibiotics, and thus lacked most of their gut microbes. Most notably, during intoxication, rats with depleted gut microbes had more activated neurons in the regions of the brain that regulate stress and pain (periaqueductal gray, locus coeruleus) and regions involved in opioid intoxication and withdrawal (central amygdala, basolateral amygdala). During withdrawal, microbe-depleted rats had fewer activated neurons in the central amygdala, as compared to rats with normal gut microbiomes."It was many months of counting black dots," Simpson said. "But in the end it became clear that, at least in rats, gut microbes alter the way the brain responds to drugs."That shift could affect behavior, she explained, because a decrease in neurons recruited in the central amygdala could result in fewer withdrawal symptoms, which can in turn lead to a higher risk of drug abuse.Now, George's team is expanding their studies to include rats that self-administer oxycodone and outbred rats that are more genetically diverse. They are also looking for microbial or chemical signatures in the rats that could indicate which are more susceptible to addiction, with and without gut microbes.In addition, the researchers are mining human microbiome data, which include users of opioids and antibiotics, to see if they follow trends similar to those they observed in rats."Not only does this study suggest gut microbes may play a role in drug addiction, if we find similar effects in humans, it may change the way we think about co-prescribing antibiotics and pain killers, for example when a person undergoes surgery," George said. "The way a person's gut microbes are affected could make them more or less sensitive to the opioids. The key now will be looking for biomarkers so we can predict how a person might respond before we treat them."As for Simpson, she earned her PhD just a week and a half ago, after successfully defending her thesis virtually -- presenting her research findings to her advisory committee, family and friends while sheltering in place during the COVID-19 pandemic. Next, Simpson will turn her attentions to a startup company she is launching to further advance and commercialize her research findings.Additional co-authors of this study include: Kokila Shankar, UC San Diego and Scripps Research; Adam Kimbrough, Brent Boomhower, Rio McLellan, Marcella Hughes, and Giordano de Guglielmo, UC San Diego.

Microbes

April 27, 2020

https://www.sciencedaily.com/releases/2020/04/200427125213.htm

Antibiotic exposure can 'prime' single-resistant bacteria to become multidrug-resistant

Antibiotics save lives -- but using them also helps antibiotic-resistant strains evolve and spread. Each year, antibiotic-resistant bacteria infect some 2.8 million people in the United States, killing more than 35,000, according to the Centers for Disease Control and Prevention. Infections by multidrug-resistant -- or MDR -- bacteria, which are resistant to two or more antibiotics, are particularly difficult to treat.

Scientists at the University of Washington and the University of Idaho have discovered just how readily MDR bacteria can emerge. In a paper published April 6 in The team's experiments indicate that prolonged exposure to one type of antibiotic essentially "primed" the bacteria. This priming effect made it more likely that the bacteria would acquire resistance to additional antibiotics, even in the absence of further antibiotic exposure, and helped the strain hold on to those antibiotic-resistance traits for generations."Exposure to antibiotics appears to select indirectly for more stable antibiotic resistance systems," said Benjamin Kerr, a UW professor of biology and co-senior author on the paper. "A more stable system in a strain will increase the chances that it will acquire resistance to multiple antibiotics."Their findings also show how antibiotic exposure affects the evolutionary dynamics within bacteria."This could help explain not only the rise of multidrug resistance in bacteria, but also how antibiotic resistance persists and spreads in the environment -- in health care settings, in soil from agricultural runoff -- even long after the antibiotic exposure has ended," said co-senior author Eva Top, a professor of biology at the University of Idaho.The researchers tested a common mechanism for the spread of antibiotic resistance: plasmids. These are circular strands of DNA that can contain many types of genes, including genes for antibiotic resistance. Bacteria easily share plasmids, even across species.Yet plasmids have their downsides, and past research has shown that bacteria readily shed them."Even though they can carry beneficial genes, plasmids can also interfere with many types of processes inside a bacterial cell, such as metabolism or DNA replication," said lead author Hannah Jordt, a UW research scientist in biology. "So, scientists have generally thought of plasmids as costly and burdensome to the host cell."The UW-University of Idaho team worked with When the researchers exposed the strains to antibiotics, growing each for 400 generations in their respective antibiotic, the strains showed greater affinity for their plasmids even after the antibiotic threat was lifted. After nine days in an antibiotic-free growth medium, more than half of "Of course, the cells needed their plasmids to help them survive the antibiotic exposure. But even after we took away that selective pressure, both strains retained their plasmids at significantly higher levels than they had before the antibiotic exposure," said Jordt.In addition, other experiments showed that antibiotic exposure increased the occurrence of MDR Prior prolonged exposure to just one antibiotic -- chloramphenicol -- had increased the likelihood that chloramphenicol-resistant Evolution can explain both the persistence of the antibiotic-resistance plasmids and the increase of MDR in "We believe that by stabilizing one plasmid, these mutations make them more likely to stabilize additionally acquired plasmids," said Kerr.Additional experiments may identify the specific mutations that helped "There are many, many details to be worked out in the future," said Top. "But what we see here is that even short-term exposure to just one antibiotic accelerates the development of multidrug resistance, which should give us pause as we use these drugs in health care, agriculture and other settings."

Microbes

April 27, 2020

https://www.sciencedaily.com/releases/2020/04/200427125145.htm

Researchers' method holds promise for brain study, better tests for viruses

University of Texas at Dallas researchers have developed a promising method for remotely stimulating activity in deep brain regions, advancing understanding of how molecules act in the brain and paving the way for better cancer treatments and therapies for other diseases.

The approach is based on the powerful combination of gold nanoparticles and lasers, which also plays a critical role in another UT Dallas research project aimed at developing a rapid diagnostic test for influenza and, possibly, the COVID-19 virus.Light is an important tool to modulate biological systems, but absorption and scattering in biological tissues significantly limit its penetration. The system developed by researchers in the Erik Jonsson School of Engineering and Computer Science and the School of Behavioral and Brain Sciences packages molecules inside microscopic gold-coated capsules, or nanovesicles, that can be very sensitive to near-infrared light.The system could solve challenges in treating diseases, such as ensuring that medication is delivered to difficult-to-reach tumors in deep brain regions while reducing damage to healthy tissue. Using that example, the nanovesicles and their cargo are injected into the brain tissue. External near-infrared lasers that penetrate the tissue cause the capsules to open and release the drug. The researchers describe the approach and results of tests in an animal model in an article published online in the chemistry journal "Our system converts light to a mechanical wave that shakes the vesicle open," said Dr. Zhenpeng Qin, assistant professor of mechanical engineering at UT Dallas and corresponding author of the study.Other researchers have used near-infrared light to trigger drug-carrying nanoparticles, such as phospholipid liposomes, which release their cargo when heated by the laser, but Qin's approach with gold-coated nanovesicles uses about 40 times less laser energy.In tests in animal models, Qin and his colleagues found that the near-infrared light penetrated 4 millimeters in the brain, which was enough to reach most targeted brain regions. Qin said he anticipates the laser penetrates far enough to reach targets deep in the rodent brain that will help answer important questions in neuromodulation."We want to improve the tests' sensitivity so that doctors can make the judgment call right in front of the patient, to be able to say either you have it or you don't have it."While the nanovesicle system must undergo more development and testing before it could be used in clinical care, Qin said the approach eventually could be applied to neurological disorders or other cancers. Dr. Hejian Xiong, research associate in Qin's lab and co-author of the journal article, received a new postdoctoral fellowship from the Phospholipid Research Center in Germany to study the use of gold-coated nanovesicles and ultra-short near-infrared lasers to target and relieve pain in patients after surgery. The project aims to provide an adjustable pain management system that could reduce the need for opioids.In a separate research project, Qin recently received a $293,000 grant from the Congressionally Directed Medical Research Programs to develop a rapid, accurate and less expensive test for infectious diseases, including influenza, that could be conducted in doctors' offices. The testing principle could also be applied to diagnose COVID-19.While many doctors conduct rapid flu tests on site, the tests can miss influenza in 30% to 50% of cases, according to the Centers for Disease Control and Prevention. Samples must be sent to a lab for an accurate diagnosis, which can take days."We want to improve the tests' sensitivity so that doctors can make the judgment call right in front of the patient, to be able to say either you have it or you don't have it," Qin said.In the testing method, gold nanoparticles are attached to antibody molecules that can recognize and bind with protein molecules found on the surfaces of viruses. Researchers apply short laser pulses to activate the nanoparticles to generate nanoscale bubbles, or nanobubbles. The accumulation of the nanobubbles signals the presence of a virus."By using optics to detect and count the nanobubbles, we can sensitively and quickly detect the presence of specific respiratory viruses," Qin said.One of the advantages of the approach is that it would not require extensive sample preparation, Qin said. The method could help doctors diagnose viruses much faster and reduce health care costs by eliminating the need for expensive lab visits. The approach could be used to detect a single virus or multiple viruses.Ultimately, researchers envision the test being broadly used in hospitals and clinics that do not have labs; however, the diagnostic method will need to be tested further before it can be made widely available.Qin's group is not working with the live coronavirus, only with viral genes, proteins and antibodies. Qin has previously obtained such patient samples for his research on respiratory syncytial virus and influenza.

Microbes

April 27, 2020

https://www.sciencedaily.com/releases/2020/04/200427091645.htm

Herpes virus decoded

Until now, scientists had assumed that there are about 80 so-called open reading frames (ORFs) in the genome of herpes simplex virus 1 (HSV-1). These are the locations in the genome where the information in the DNA is read and translated into proteins. It is now clear that there are a lot more -- namely 284 ORFs. These are translated from hundreds of novel viral transcripts, which have now also been identified.

This is what research groups from Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany, and other institutions report in the journal "The new findings now make it possible to study the individual genes of the virus much more precisely than before," says Professor Lars Dölken, head of the JMU Chair of Virology. He was in charge of this project together with Florian Erhard, JMU junior professor of systems virology.The research team used a broad spectrum of the latest systems biology methods for the study. In addition to JMU, the Max Delbrück Center for Molecular Medicine in Berlin, the University of Cambridge in England and Ludwig-Maximilians-Universität of Munich were involved.The data are not only important for a better understanding of the virus itself. They also have concrete implications, for example for the development of HSV-1-based oncolytic viruses. These are viruses that are used in immunological therapies of certain tumor diseases, such as malignant melanoma.Herpes simplex viruses of type 1 (HSV-1) are known to many people as the cause of unpleasant itching cold sores. An infection with this virus type can also have serious consequences. For example, HSV-1 can cause life-threatening pneumonia in patients in intensive care units. And in healthy people, it can cause encephalitis, which often leads to permanent brain damage.Once infected with the virus, a person will retain it for the rest of his or her life: herpes viruses permanently nestle in body cells. There they usually remain inconspicuous for a long time. Only under special circumstances, such as a weakened immune system, they become active again.Lars Dölken researches herpes viruses very intensively. For his successes in this field he was awarded a Consolidator Grant by the European Research Council in 2016. The prize was endowed with around two million euros; the money will go towards studies on herpes viruses.

Microbes