Diagnostic developers target antibiotic resistance

When a patient shows up at the clinic with a cough and sore throat, there is no good way of discovering whether the infection is bacterial or viral. As a result, many clinicians prescribe antibiotics without really knowing if the drugs are necessary — a situation that contributes to the worrying rise of antibiotic resistance. But a team of researchers has collected evidence to suggest that by tracking the genetic signature of a patient’s immune response to infection, they will be able to distinguish bacterial infections from other sources of illness.

Rapid-detection tests or throat cultures that are used to detect streptococcus and other common bacteria can miss more than 50% of infections and are plagued with false positives. The resulting overuse of antibiotics contributes to antibiotic resistance, a growing public-health threat. The US Centers for Disease Control and Prevention estimates that antibiotic-resistant infections kill at least 23,000 people each year in the United States. And in India, the percentage of Klebsiella pneumoniae infections that are resistant to powerful carbapenem drugs rose from 29% in 2008 to 57% in 2014.

The Duke team’s hypothesis — that specific changes in gene activity might betray the type of infection that the body is responding to — is a reasonable one, says David Relman, a microbiologist at Stanford University in California. “It’s not terribly likely that the host response alone will be sufficient for identifying the pathogen, but it could be used to predict a class of illness and help clinicians decide on a general treatment approach,” Relman says.

Over six years, the Duke team collected blood samples from more than 300 patients who came to the hospital with symptoms consistent with a viral or bacterial infection. Retrospectively, the researchers determined which patients actually had which kind of infection and analysed the genes expressed in the immune cells from the blood samples.

“There are a number of groups working in this area that just a few years back were laughing at us,” notes Woods. “Most people didn’t believe this was a useful approach.” But the team was able to show that the gene-expression patterns reliably distinguished between bacterial and viral or non-infectious illness. “The signal was terrific,” Ginsburg says.

In the last decade, improvements in methods for measuring the expression of many genes at once, accompanied by the development of new statistical methods to analyse the data, were crucial to the team’s success.

The real challenge now, the researchers say, is to transform this research into a clinical tool. The focus of the FDA workshop, explains the FDA’s infectious-disease specialist Steven Gitterman, will be to consider the performance standards to which these new technologies should be held and to develop appropriate clinical-trial designs to evaluate their safety and accuracy.

A rigorous clinical validation of this type of diagnostic would take a lot of time and resources, Relman predicts, because it would have to show that different populations around the world all respond similarly to bacterial infections.

The technology also needs to deliver information in a clinically relevant time frame, the researchers say. The team is working with industry partners to develop a platform that can reduce the time required to measure the genes of interest from days to an hour or less. If that goal can be achieved, says Woods, “that changes how we deal with patients altogether”.

Nature doi:10.1038/nature.2015.18512  Nature  Original web page at Nature


Drug-resistant E. coli continues to climb in community health settings

Drug-resistant E. coli infections are on the rise in community hospitals, where more than half of U.S. patients receive their health care, according to a new study from Duke Medicine.

The study reviewed patient records at 26 hospitals in the Southeast. By examining demographic information, admission dates and tests, the researchers also found increased antibiotic-resistant infections among community members who had limited exposure to health care settings, but who may have acquired the bugs through some other environmental factors. The findings are published online in Infection Control & Hospital Epidemiology.

“We have always considered antibiotic-resistant organisms a problem at large hospitals,” said Deverick Anderson, M.D., an infectious disease specialist at Duke University School of Medicine and senior author of the study. “This study goes a long way in demonstrating that the problems with antibiotic-resistant organisms occur in all health care settings, not just large ones. This is also one of the first papers to show these infections are increasing outside of the health care system in the community.”

“The larger issue speaks to antibiotics,” Anderson said. “Antibiotics are extremely important and useful in medical care, but we know we overuse them.”

The study data were gathered through the Duke Infection Control Network (DICON), which helps community hospitals and surgery centers across the U.S. prevent infections using education and evidence-based strategies.

The data showed that between 2009 and 2014, the incidence of drug-resistant extended-spectrum beta-lactamase (ESBL)-producing E. coli doubled from a rate of 5.28 incidents per 100,000 patients to a rate of 10.5 infections per 100,000. The median age of patients infected with E. coli was 72 years.

“Overall, the majority of E. coli infections occurred after health care exposure, which makes all hospitals, big and small, important areas of focus to reduce transmission,” said lead author Joshua Thaden, M.D., a fellow in Duke’s Division of Infectious Diseases. “It’s important to consider that a patient’s skin may be colonized with drug-resistant bacteria, but because they do not display symptoms, providers may not test them or use extensive contact precautions during care. I think we may be close to a point where it becomes worth the cost and effort to actively screen patients for resistant E. coli.”

Looking at the timing of patients’ infections and when they were last in contact with a health care setting, the researchers also discovered that people with infrequent health care contact were acquiring the superbug at an even faster rate than patients who have regular contact with hospitals or nursing homes. The data showed a greater than three-fold increase in community-associated infections between 2009 and 2014. The sources could be environmental and need further study, Thaden said.  Science Daily  Original web page at Science Daily


The tantalizing links between gut microbes and the brain

Neuroscientists are probing the idea that intestinal microbiota might influence brain development and behaviour.

Nearly a year has passed since Rebecca Knickmeyer first met the participants in her latest study on brain development. Knickmeyer, a neuroscientist at the University of North Carolina School of Medicine in Chapel Hill, expects to see how 30 newborns have grown into crawling, inquisitive one-year-olds, using a battery of behavioural and temperament tests. In one test, a child’s mother might disappear from the testing suite and then reappear with a stranger. Another ratchets up the weirdness with some Halloween masks. Then, if all goes well, the kids should nap peacefully as a noisy magnetic resonance imaging machine scans their brains.

“We try to be prepared for everything,” Knickmeyer says. “We know exactly what to do if kids make a break for the door.”

Knickmeyer is excited to see something else from the children — their faecal microbiota, the array of bacteria, viruses and other microbes that inhabit their guts. Her project (affectionately known as ‘the poop study’) is part of a small but growing effort by neuroscientists to see whether the microbes that colonize the gut in infancy can alter brain development.

The project comes at a crucial juncture. A growing body of data, mostly from animals raised in sterile, germ-free conditions, shows that microbes in the gut influence behaviour and can alter brain physiology and neurochemistry.

In humans, the data are more limited. Researchers have drawn links between gastrointestinal pathology and psychiatric neurological conditions such as anxiety, depression, autism, schizophrenia and neurodegenerative disorders — but they are just links.

“In general, the problem of causality in microbiome studies is substantial,” says Rob Knight, a microbiologist at the University of California, San Diego. “It’s very difficult to tell if microbial differences you see associated with diseases are causes or consequences.” There are many outstanding questions. Clues about the mechanisms by which gut bacteria might interact with the brain are starting to emerge, but no one knows how important these processes are in human development and health.

That has not prevented some companies in the supplements industry from claiming that probiotics — bacteria that purportedly aid with digestive issues — can support emotional well-being. Pharmaceutical firms, hungry for new leads in treating neurological disorders, are beginning to invest in research related to gut microbes and the molecules that they produce.

Scientists and funders are looking for clarity. Over the past two years, the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, has funded seven pilot studies with up to US$1 million each to examine what it calls the ‘microbiome–gut–brain axis’ (Knickmeyer’s research is one of these studies). This year, the US Office of Naval Research in Arlington, Virginia, agreed to pump around US$14.5 million over the next 6–7 years into work examining the gut’s role in cognitive function and stress responses. And the European Union has put €9 million (US$10.1 million) towards a five-year project called MyNewGut, two main objectives of which target brain development and disorders.

The latest efforts aim to move beyond basic observations and correlations — but preliminary results hint at complex answers. Researchers are starting to uncover a vast, varied system in which gut microbes influence the brain through hormones, immune molecules and the specialized metabolites that they produce.

“There’s probably more speculation than hard data now,” Knickmeyer says. “So there’s a lot of open questions about the gold standard for methods you should be applying. It’s very exploratory.”

Microbes and the brain have rarely been thought to interact except in instances when pathogens penetrate the blood–brain barrier — the cellular fortress protecting the brain against infection and inflammation. When they do, they can have strong effects: the virus that causes rabies elicits aggression, agitation and even a fear of water. But for decades, the vast majority of the body’s natural array of microbes was largely uncharacterized, and the idea that it could influence neurobiology was hardly considered mainstream. That is slowly changing.

Studies on community outbreaks were one key to illuminating the possible connections. In 2000, a flood in the Canadian town of Walkerton contaminated the town’s drinking water with pathogens such as Escherichia coli and Campylobacter jejuni. About 2,300 people suffered from severe gastrointestinal infection, and many of them developed chronic irritable bowel syndrome (IBS) as a direct result.

During an eight-year study of Walkerton residents, led by gastroenterologist Stephen Collins at McMaster University in Hamilton, Canada, researchers noticed that psychological issues such as depression and anxiety seemed to be a risk factor for persistent IBS. Premysl Bercik, another McMaster gastroenterologist, says that this interplay triggered intriguing questions. Could psychiatric symptoms be driven by lingering inflammation, or perhaps by a microbiome thrown out of whack by infection?

The McMaster group began to look for answers in mice. In a 2011 study, the team transplanted gut microbiota between different strains of mice and showed that behavioural traits specific to one strain transmitted along with the microbiota. Bercik says, for example, that “relatively shy” mice would exhibit more exploratory behaviour when carrying the microbiota of more-adventurous mice. “I think it is surprising. The microbiota is really driving the behavioural phenotype of host. There’s a marked difference,” Bercik says. Unpublished research suggests that taking faecal bacteria from humans with both IBS and anxiety and transplanting it into mice induces anxiety-like behaviour, whereas transplanting bacteria from healthy control humans does not.

Such results can be met with scepticism. As the field has developed, Knight says, microbiologists have had to learn from behavioural scientists that how animals are handled and caged can affect things such as social hierarchy, stress and even the microbiome.

There is much more to unravel, she says. “I’m always surprised. It’s very open. It’s a little like a Wild West out there.” Read more:

Nature 526, 312–314 (15 October 2015) doi:10.1038/526312a  Nature Original web page at Nature


* Global burden of leptospirosis is greater than thought, and growing

The global burden of a tropical disease known as leptospirosis is far greater than previously estimated, resulting in more than 1 million new infections and nearly 59,000 deaths annually, a new international study led by the Yale School of Public Health has found.

Professor Albert Ko, M.D., and colleagues conducted a systematic review of published morbidity and mortality studies and databases, and for the first time developed a disease model to generate a worldwide estimate of leptospirosis’ human toll. The results were published Sept. 17 in PLOS Neglected Tropical Diseases.

While leptospirosis is relatively unknown in the developed world, it is a growing scourge in resource-poor settings throughout Latin America, Africa, Asia, and island nations. The spirochetal bacteria that causes the disease is shed in the urine of rats and other mammals. The pathogen survives in water and soil and infects humans upon contact through abrasions in the skin.

The finding shows leptospirosis is one of the leading zoonotic (diseases passed between animals and humans) causes of morbidity and mortality in the world and is a call to action, said Ko, chair of the Department of Epidemiology (microbial disease) at Yale School of Public Health.

“The study identified an important health burden caused by this life-threatening disease, which has been long neglected because it occurs in the poorest segments of the world’s population,” said Ko, who has studied the disease for years in Brazil’s urban slum communities, or favelas. “At present, there are no effective control measures for leptospirosis. The study provides national and international decision-makers with the evidence to invest in initiatives aimed at preventing the disease, such as development of new vaccines, as well as targeting the underlying environmental and social conditions, rooted in social inequity, that lead to its transmission.”

The researchers said that the incidence of the disease has the potential to grow even further in the coming decades due to global climate change and rapid urbanization. The disease is particularly prevalent in urban slums where inadequate sewerage and sanitation, combined with extreme climatic events and heavy seasonal rainfall, enhance contact with contaminated environments, causing epidemics. It is estimated that the world’s slum population will double to 2 billion people by 2030.

Leptospirosis results in severe illness and has emerged as an important cause of pulmonary hemorrhage and acute renal failure in developing countries, where death occurs in 10% of patients, and hemorrhaging occurs in up to 70%.

It is likely that the latest numbers still underestimate the problem, the researchers noted, as leptospirosis patients are frequently misdiagnosed with malaria, dengue, or other illnesses. There is also not an adequate diagnostic test for the disease.

Prior inconclusive estimates of the leptospirosis burden have contributed to its status as a neglected tropical disease and hampered efforts to develop effective prevention and control measures, the researchers said.  Science Daily  Original web page at Science Daily


Superbug study reveals how E. coli strain acquired deadly powers

A strain of E. coli became a potentially fatal infection in the UK around 30 years ago, when it acquired a powerful toxin, a gene study has revealed. The discovery helps to explain outbreaks of severe food poisoning that began in the 1980s. Scientists say their findings show that E. coli O157 is continuing to evolve and should be monitored closely. Most strains of E. coli are harmless and live in the guts of people and animals without causing illness.

E. coli O157 strains can produce molecules called shiga-toxins, which are linked to more serious human infections. The strains that are responsible for the majority of serious illness in people in the UK produce two types of shiga-toxin — stx1 and stx2a.

A team of researchers — including scientists at Public Health England and the University of Edinburgh — decoded the genetic sequences of more than a thousand samples of E. coli O157 collected from human infections and animals over the past 30 years. Their analysis reveals that the ancestor of E. coli O157 has been around for more than 175 years. They found that most of the ancestor strains carry only stx1 but some strains began to acquire stx2a around 60 years ago. The dangerous strains of E. coli O157 that have caused most illness in people in the UK acquired stx2a around three decades ago, when outbreaks of severe food poisoning began to appear.

Some more recent infections are being caused by E. coli O157 strains that carry only stx2a. Early evidence suggests that these strains may be even more dangerous than those to date.

Cows are the main reservoir of E. coli O157, though they show no signs of the disease. Animals that are infected with strains that produce stx2a excrete higher levels of dangerous bacteria in their manure. This helps to spread infection between animals and increases the chances of the bacteria being passed to people.

Professor David Gally, of the University of Edinburgh’s Roslin Institute, said: “Thankfully, dangerous E. coli outbreaks remain relatively rare. Our research underlines the need to study the genetic code of strains that cause infections in humans and those present in farmed animals.

“Good hygiene practices — both with food and when out enjoying the countryside — can help to minimise the risk of these and other severe infections. Our work endeavours to understand how these toxic strains persist in cattle and the best ways to prevent them spreading to us.”  Science Daily  Original web page at Science Daily


Viruses join fight against harmful bacteria

In the hunt for new ways to kill harmful bacteria, scientists have turned to a natural predator: viruses that infect bacteria. By tweaking the genomes of these viruses, known as bacteriophages, researchers hope to customize them to target any type of pathogenic bacteria.

To help achieve that goal, MIT biological engineers have devised a new mix-and-match system to genetically engineer viruses that target specific bacteria. This approach could generate new weapons against bacteria for which there are no effective antibiotics, says Timothy Lu, an associate professor of electrical engineering and computer science and biological engineering.

“These bacteriophages are designed in a way that’s relatively modular. You can take genes and swap them in and out and get a functional phage that has new properties,” says Lu, the senior author of a paper describing this work in the Sept. 23 edition of the journal Cell Systems.

These bacteriophages could also be used to “edit” microbial communities, such as the population of bacteria living in the human gut. There are trillions of bacterial cells in the human digestive tract, and while many of these are beneficial, some can cause disease. For example, some reports have linked Crohn’s disease to the presence of certain strains of E. coli.

“We’d like to be able to remove specific members of the bacterial population and see what their function is in the microbiome,” Lu says. “In the longer term you could design a specific phage that kills that bug but doesn’t kill the other ones, but more information about the microbiome is needed to effectively design such therapies.”

The Food and Drug Administration has approved a handful of bacteriophages for treating food products, but efforts to harness them for medical use have been hampered because isolating useful phages from soil or sewage can be a tedious, time-consuming process. Also, each family of bacteriophages can have a different genome organization and life cycle, making it difficult to engineer them and posing challenges for regulatory approval and clinical use.

The MIT team set out to create a standardized genetic scaffold for their phages, which they could then customize by replacing the one to three genes that control the phages’ bacterial targets.

Many bacteriophages consist of a head region attached to a tail that enables them to latch onto their targets. The MIT team began with a phage from the T7 family that naturally kills Escherichia coli. By swapping in different genes for the tail fiber, they generated phages that target several types of bacteria. “You keep the majority of the phage the same and all you’re changing is the tail region, which dictates what its target is,” Lu says.

To find genes to swap in, the researchers combed through databases of phage genomes looking for sequences that appear to code for the key tail fiber section, known as gp17. After the researchers identified the genes they wanted to insert into their phage scaffold, they had to create a new system for performing the genetic engineering. Existing techniques for editing viral genomes are fairly laborious, so the researchers came up with an efficient approach in which they insert the phage genome into a yeast cell, where it exists as an “artificial chromosome” separate from the yeast cell’s own genome. During this process the researchers can easily swap genes in and out of the phage genome.

“Once we had that method, it allowed us very easily to identify the genes that code for the tails and engineer them or swap them in and out from other phages,” Lu says. “You can use the same engineering strategy over and over, so that simplifies that workflow in the lab.”

In this study, the researchers engineered phages that can target pathogenic Yersinia and Klebsiella bacteria, as well as several strains of E. coli. These are all part of a group known as Gram-negative bacteria, against which there are few new antibiotics. This group also includes microbes that can cause respiratory, urinary, and gastrointestinal infections, including pneumonia, sepsis, gastritis, and Legionnaires’ disease

One advantage of the engineered phages is that unlike many antibiotics, they are very specific in their targets. “Antibiotics can kill off a lot of the good flora in your gut,” Lu says. “We aim to create effective and narrow-spectrum methods for targeting pathogens.

Lu and his colleagues are now designing phages that can target other strains of harmful bacteria, which could have applications such as spraying on crops or disinfecting food, as well as treating human disease. Another advantage of this approach is that all of the phages are based on an identical genetic scaffold, which could streamline the process of getting regulatory approval, Lu says.  Science Daily  Original web page at Science Daily


Whale microbiome shares characteristics with both ruminants, predators

To some, it may not come as a surprise to learn that the great whales are carnivores, feeding on tiny shrimp-like animals such as krill. Moreover, it might not be surprising to find that the microbes that live in whale guts -the so-called microbiome- resemble those of other meat eaters. But scientists now have evidence that the whales’ microbiome shares traits with creatures not known to eat meat — cows.

Led by Peter Girguis, Professor of Organismic and Evolutionary Biology, scientists have found that the gut microbiome of right whales and other baleen species shares characteristics with both cows and meat-eating predators. The dual microbial communities allow whales to extract the most nutrition possible from their diet, digesting not only the copepods they eat, but their chitin-rich shells as well. The study is described in a September 22 paper in Nature Communications.

“From one point of view, whales look like carnivores,” Girguis said. “They have the same kind of microbes that we find in lions and tigers that have very meat-rich diets. But they also have abundant communities of anaerobic bacteria, similar to those that ruminants use to break down cellulose.

“However, there’s not a lot of cellulose in the ocean, but there is a lot of chitin, which is in the exoskeletons of copepods that baleen whales eat,” Girguis continued. “What our paper suggests is the whale foregut is much like a cow’s gut, and we posit that chitin-degrading anaerobic microbial community thrives in there, breaking down that material and making it available to the whale.”

Those exoskeletons, Girguis said, represent as much as ten percent of whale’s total food intake, and would otherwise simply be defecated. By allowing whales to access the nutrition in the chitin-rich material, whales are able to extract the most possible benefit from their diet.

“It’s almost like a pre-adaptation,” he said “that may give them a differential advantage in harnessing energy from their food. The morphology of their gut comes from their ancestors, the very same ancestors to cows, camels and other ruminants. It serves them well even as carnivores because it allows them to maximally extract nutrition from their food.”

Ultimately, Girguis said, the study addresses questions that reach far beyond the guts of whales. “This is really a question of what we can call phylogenetic inertia,” he said. “Because what we’re really thinking about is: When you look at the microbiome of an organism, you can -to some degree- look back in time and see its ancestors, because organisms that are related to one another seem to have similar microbiomes.

“But not all organisms that are related live in the same kind of environment,” he continued. “So the question is how different does your environment need to be before it changes your microbiome? This is a fundamental question about the relationship between your ancestry versus your current environment.” Many of those questions, however, might not have been asked, Girguis said, were it not for then-undergraduate student Annabel Beichman.

Now a graduate student at UCLA and the second author of the study, Beichman kick-started the study when she and University of Vermont conservation biologist Joe Roman took on the unenviable task of following pods of right whales at sea and collecting samples of their feces to determine which microbes were present. “There’s no other way to get the fecal samples but to collect them from the ocean,” Roman said.

“It was a thrill to set out each morning into uncertain weather to search for elusive right whales, then to extract and sequence DNA from our smelly trophies,” Beichman said. “It had always been my passion to use the latest advances in genetic sequencing technology to answer questions about species of conservation concern, and so I wanted to add a genetic component to the study.

“Working with my advisors to conceive the research questions based on the scientific literature, collect fecal samples in the field, and carry out DNA sequencing and analysis gave me invaluable experience at every stage of the study,” she added. “We all had different theories as to what the whale gut community might look like. What none of us expected was to see so much divergence from terrestrial mammals, or these shared characteristics with both terrestrial carnivores’ and herbivores’ microbiomes.”

“Given what we know about whales’ ancestry — that they’re related to ruminants, and that they still have a multi-chambered foregut — there were several things we might find,” Girguis said. “One hypothesis was that their microbiome would look like those of other meat-eaters like lions and tigers, and the foregut was just vestigial. The other hypothesis was that it allowed a different group of microbes to do something we hadn’t thought about. What we found was that whales have a microbiome that looks halfway like a ruminant and halfway like a carnivore.

“We’ve come to better understand the evolution of whales over the past few decades, and see where they fit on the evolutionary tree. But we have not understood the microbial changes that have allowed them to become one of the most successful groups of animals in the ocean,” said Roman. “This study helps explain that.”

Going forward, Girguis and colleagues hope to sample the microbial community in whales’ stomach chambers, and to extend the study to toothed whales, which don’t have such chitin-rich diets. The team has also received interest from aquariums, which may be able to use information about the gut microbes in whales in order to better care for animals kept in captivity.

“A lot of aquariums…they know when their whales are healthy or not, but they don’t always have a causal factor, and these gut microbes may be a big clue,” Girguis said. “As long as people keep whales in captivity, there is value in this type of research, because it can keep them as healthy as possible.”

While it may not provide a definitive answer to questions of phylogenetic inertia, the study does suggest that some morphological features, if they can provide an advantage, are retained, despite dramatic changes in a creature’s environment.

“We now have this snapshot that addresses this question of how a creature’s evolutionary past interacts with its microbiome, and how their diet today influences their microbiome,” he said. “The answer is…if that morphological feature, if it has value to a species, then it may well be something that’s capitalized on over evolutionary time.   Science Daily  Original web page at Science Daily


Humans carry more antibiotic-resistant bacteria than animals they work with

Low potential health risk posed to workers in close contact with dairy herds and milk consumers through exposure to antibiotic-resistant staphylococci originating from milk.

Antibiotic-resistant bacteria are a concern for the health and well-being of both humans and farm animals. One of the most common and costly diseases faced by the dairy industry is bovine mastitis, a potentially fatal bacterial inflammation of the mammary gland (IMI). Widespread use of antibiotics to treat the disease is often blamed for generating antibiotic-resistant bacteria. However, researchers investigating staphylococcal populations responsible for causing mastitis in dairy cows in South Africa found that humans carried more antibiotic-resistant staphylococci than the farm animals with which they worked. The research is published in the Journal of Dairy Science®.

Animal agriculture is often blamed for generating antibiotic-resistant bacteria through the “widespread” use of antibiotics. “South Africa has one of the highest HIV/AIDS and tuberculosis rates in the world and the human health risk to immune-compromised individuals is therefore that much greater,” explained lead investigator Tracy Schmidt, a PhD candidate at the Department of Medical Microbiology, University of Pretoria, and a veterinary researcher at the KwaZulu-Natal (KZN) provincial Department of Agriculture and Rural Development in South Africa. “The rise of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) and reported cases of bacterial transmission between dairy cows and humans has raised concerns from both the agriculture/veterinary sector and public health officials. The lack of data about the occurrence of LA-MRSA in South Africa and the need to investigate possible reservoirs were part of the motivation for this work.”

Staphylococcus aureus is a contagious udder pathogen that readily spreads between cows at milking. The main source is milk from infected quarters, with milking machine teat liners playing a significant role in the transmission of the bacteria among cows and mammary quarters. Infected cows need to be promptly identified and appropriate control measures need to be taken to curb bacterial transmission among cows. Other Staphylococcus species, collectively referred to as coagulase-negative staphylococci (CNS), have traditionally been regarded as opportunistic pathogens of minor importance as mastitis caused by these bacteria is usually mild and remains subclinical However, the significance of CNS is being reassessed because, in many countries including South Africa, CNS have become the most common bacteria isolated from bovine IMI. Also of great importance is the fact that CNS often exhibit extensive resistance to antimicrobials and may serve as a reservoir of resistance genes that can transfer and supplement the genome of more pathogenic bacteria like Staphylococcus aureus.

This research in the KwaZulu-Natal province of South Africa investigated the diversity of Staphylococcus populations responsible for IMI in dairy cows and assessed the susceptibility of different species to antimicrobials commonly used in the veterinary field as well as human medicine. At the same time, individuals working in close contact with the animals were sampled and the diversity and susceptibility profiles of staphylococcal isolates determined and compared with isolates of animal origin.

With respect to staphylococcal diversity the results showed the clear predominance of Staphylococcus chromogenes among the CNS causing IMI, while Staphylococcus epidermidis was the isolate most commonly recovered from the human specimens.

The study found a relatively low occurrence of antimicrobial resistance among the bovine staphylococci. “This is encouraging as it indicates the responsible usage of antimicrobials within local dairies and provides our veterinary practitioners and animal owners valuable information going forward with respect to the treatment of infected animals,” commented Schmidt. None of the staphylococcal isolates of bovine origin were found to be resistant to methicillin. Furthermore, all isolates tested negative for the presence of vancomycin-encoding genes — vancomycin being one of the front-line antimicrobials used for the treatment of methicillin-resistant staphylococcal infections in humans. The results indicate the low potential health risk posed to close contact workers and milk consumers through exposure to antibiotic-resistant staphylococci originating from milk.

“Of greatest interest was the extensive antimicrobial resistance noted among the coagulase-negative staphylococci of human origin. Multidrug resistance was common among isolates, and due to the propensity for staphylococci to acquire antimicrobial resistance through genetic exchange, human staphylococci can be regarded as a potential reservoir of resistance genes,” added Schmidt.

“As an industry we are making great strides to reduce the use of blanket treatment of farm animals with antibiotics and the notion that antibiotic-resistant bacteria are moving from farm animals to humans has been debunked many times,” observed Matt Lucy, PhD, Professor of Animal Science at the University of Missouri and Editor-in-Chief of the Journal of Dairy Science. “What the authors found is that the humans working with farm animals carry far more antibiotic-resistant staphylococci that the farm animals they work with. The risk, therefore, is the transfer from humans to farm animals and not from farm animals to humans as is often suggested.”  Science Daily  Original web page at Science Daily


* Success combating multi-resistant bacteria in stables

Multi-resistant bacteria represent a major problem not only in hospitals but also in animal husbandry. A study of the University Bonn describes how a farmer successfully eliminated these pathogens entirely from his pig stable. However, the radical hygiene measures taken in this case can only be applied in individual cases. Nevertheless, the work has yielded a number of recommendations — not only for farms but also for hospitals. The study appeared in the Journal of Applied and Environmental Microbiology.

Today some farms are implementing measures more frequently found in an operating theater: To enter the stable, employees have to change clothes. Before and after visiting the stables, hands must be cleaned thoroughly. Newly purchased animals are quarantined immediately. Particularly careful farmers arrange regular microbiological screens for resistant bacteria for themselves and their staff.

The purpose of these measures is to prevent the spread of dangerous pathogens — in particular multi-drug-resistant bacteria. Under certain circumstances these bacteria are dangerous, because infections are difficult to treat with antibiotics. Two major problems are posed by methicillin resistant Staphylococcus aureus (MRSA), and certain intestinal bacteria which produce extended-spectrum beta-lactamases (ESBL). Even the strictest precautions against these bacteria are often not 100 percent successful, because these pathogens are found not only in humans and animals but also on walls and even in the air of the stable. In a previous study, researchers at the University of Bonn found MRSA on every fifth pig, and an ESBL rate of 30 percent.

For the first time, researchers have successfully demonstrated that multi-resistant bacteria can be eradicated from a stable. “But these radical steps can only be implemented in very few cases,” says the agronomist Dr. Ricarda Schmithausen of the University of Bonn. As part of the study, the stables of the farmer were completely renovated and an additional new stable was built. The measures were accompanied by a multi-level disinfection process.

This would have been impossible during the daily routine. The farmer had planned a conversion of his farming system and therefore had previously slaughtered his entire herd and then restocked with pigs. The newly purchased animals were tested randomly to prevent the introduction of new resistant bacteria. The measures were successful, according to Dr. Schmithausen: “Today, two years after decontamination, the farm is still ESBL-free. MRSA, unfortunately, was a different story: Only two days later another MRSA variant was detected. Presumably, the new MRSA bacteria were introduced by one of the animals. In spite of all tests this cannot be avoided.” Nevertheless, the health of the herd has improved significantly. As a result, the use of antibiotics is hardly necessary any more.

MRSA are first and foremost pathogenic for humans and are largely harmless for animals. Previous studies by the University of Bonn have shown that farmers carry multi-resistant bacteria more often than the general population — as a result of their close contact with animals. The colonisation remains mostly asymptomatic for farmers. However, it can be dangerous, if the pathogens are transmitted to immuno-compromised patients in hospitals.

The agronomist and physician Dr. Ricarda Schmithausen defends the farmers. “Most cooperating farmers are very well informed and act very responsibly concerning this issue by implementing high hygiene standards” she emphasizes. The risk that MRSA and ESBL-E bacteria will spread further can be minimized through normal measures but cannot be reduced to zero. “Hospitals and livestock farms fight the same problems,” she says. “Both sides can learn from each other — hospitals could, for example, screen inpatients more consistently for multi-resistant bacteria. Science Daily  Original web page at Science Daily


‘Clever adaptation’ allows yeast infection fungus to evade immune system attack

Discovery offers clues about why some Candida albicans infections are so deadly Johns Hopkins Bloomberg School of Public Health researchers say they have discovered a new way that the most prevalent disease-causing fungus can thwart immune system attacks. The findings, published Sept. 7 in the Proceedings of the National Academy of Sciences, offer new clues about how Candida albicans, the fungus responsible for vaginal yeast infections and the mouth infection thrush, is able to cause a deadly infection once it enters the bloodstream.

When the body is faced with an infection, cells give a burst of free radicals to kill the germs. C. albicans and other fungi use copper to fuel an enzyme designed to neutralize the free radical attack. But once the body senses the presence of the fungal infection, it flushes copper into the bloodstream to fight, leaving copper-starved fungus in the tissues in places like the kidney.

But instead of being thwarted by a lack of copper to feed its defense, the Johns Hopkins team has discovered that C. albicans has uniquely evolved to switch from using copper to counter the free radicals to using the metal manganese. “What we have found here is a very clever adaptation to changes in copper during infection,” says study leader Valeria C. Culotta, PhD, a professor in the Department of Biochemistry and Molecular Biology at the Bloomberg School. “The more we learn about this pathogen’s ability to survive inside a human, the more points of vulnerability we may identify.

  1. albicans only has the potential to become lethal to humans once it enters the bloodstream, where it can then affect the liver, spleen and kidneys. People with compromised immune systems such as premature babies, chemotherapy patients and those with HIV are particularly vulnerable to this and can die of the kidney failure it causes.

Using a mouse model for C. albicans, Culotta and her team sought to understand why the pathogen switches between copper and manganese to fight free radicals. They discovered a surprising role for copper in immunity — levels of copper in the bloodstream go through the roof during infection in an attempt to kill the pathogen with copper poisoning. Organs such as the kidneys send their copper into the bloodstream, causing their levels to drop

The story would likely end there, if not for the switch the fungus makes in how it protects itself, one of the Johns Hopkins team’s new discoveries. In an unexpected twist, the enzyme C. albicans uses to counter the free radicals changes from one that requires copper to one that requires manganese. The fungus can then use manganese to neutralize the attack.

“The fungus laughs in the face of this loss in copper by simply switching metals,” Culotta says. “Somehow this fungus has evolved to adapt to this immune system attack. This allows C. albicans to survive when other organisms might be thwarted.”

Copper and manganese are both found in relatively small quantities in the human body. Copper mainly comes from the consumption of crustaceans such as lobster and crab and from vegetables grown in copper-containing soil. Manganese is found in whole grains, nuts, leafy vegetables and teas.

Copper is known to fight off the spread of bacteria. In the United Kingdom, for example, many hospitals have switched out steel doorknobs for copper ones. The pathogens can’t live on the surface of the copper knobs, dramatically reducing the spread of infections.

Current antifungal medications work on the surface of the cell to destroy the fungus. But there is a growing problem of human resistance to antifungal medications, similar to the well-known issue of antibiotic resistance. Just as has happened with some antibiotics, some fungi have evolved with the overuse of current antifungal medications and may no longer respond to the drugs designed to cure them. Culotta says there may be some way to design drugs in the future to disrupt the process whereby C. albicans switches from using a copper-based enzyme to a manganese-based one . Science Daily  Original web page at Science Daily


Urgent action needed to protect salamanders from deadly fungus, scientists warn

A deadly fungus identified in 2013 could devastate native salamander populations in North America unless U.S. officials make an immediate effort to halt salamander importation, according to an urgent new report published today in the journal Science.

San Francisco State University biologist Vance Vredenburg, his graduate student Tiffany Yap and their colleagues at the University of California, Berkeley and the University of California, Los Angeles say the southeastern United States (particularly the southern extent of the Appalachian Mountain range and its southern neighboring region), the Pacific Northwest and the Sierra Nevada, and the central highlands of Mexico are at the highest risk for salamander declines and extinctions if the fatal Batrachochytrium salamandrivorans (Bsal) fungus makes its way into those regions.

Salamanders are popular worldwide as pets, and frequently traded across borders. That has scientists worried that the fungus could spread from Asia, where it likely originated, to other parts of the globe. Vredenburg and his coauthors on the study are asking the U.S. Fish and Wildlife Service to place an immediate ban on live salamander imports to the U.S. until there is a plan in place to detect and prevent the spread of Bsal. Although the ban has been supported by key scientists for some time, including in a prominent op-ed in the New York Times last year, the government has been slow to act.

“This is an imminent threat, and a place where policy could have a very positive effect,” Vredenburg said. “We actually have a decent chance of preventing a major catastrophe.”

Salamanders are one of the most abundant vertebrate animals in many North American ecosystems and play a number of key ecological roles. “They are very important predators of insects, but also an important part of the food chain,” noted Vredenburg, an associate professor of biology.

Bsal likely originated in Asian species of salamander that are traded as popular pets around the world. When the fungus made its way into Europe through the pet trade, it caused a 96 percent fatality rate among the European salamander species that it infected. It was also fatal to American salamanders exposed to the fungus in the lab.

The blue-tailed fire-bellied newt (Cynops cyanurus), the Japanese fire-bellied newt (Cynops pyrrhogaster), and the Tam Dao or Vietnamese salamander (Paramesotriton deloustali) are thought to be the main carriers of Bsal. Alarmingly, 91 percent of pet salamanders imported to North America come from either the Cynops or Paramesotriton groups.

“We’ve made specific predictions, on the ground, of where North American species are most vulnerable to Bsal,” said Vredenburg. “And the places that have the highest amount of trade in these salamanders happen to be in those high-risk areas.

To map out high-risk regions of Bsal infection in North America, the research team looked at habitats where the fungus might thrive, based on its Asian carrier locations, along with data on how many different species might be threatened in those areas and the location of major U.S. ports of entry for salamander trade between 2010 and 2014

Vredenburg fears that the salamanders might be on the verge of an ecological crisis that is all too familiar to him. For more than a decade he has studied the impact of a similarly deadly fungus called Batrachochytrium dendrobatidis (Bd). More than 200 species of amphibians have gone extinct or are near to extinction as a result of Bd infection, making it the most devastating infectious wildlife disease ever recorded.

“I have seen the effects of Bd on frogs, to the point where I’ve seen tens of thousands of animals die in the wild in pristine areas, here in California, right in front of my eyes,” Vredenburg said. “It is just an unbelievable sight to see all these dead animals.”

The heartbreaking work might have a silver lining, he said, if it can be used to save the salamanders from a similar plight.

“One of the things that I find remarkable about this is that unlike when we first figured out what was going on with Bd, no one could even imagine that one pathogen could cause so much damage across all these different species, because we had never seen anything like that ever before,” Vredenburg said. “What’s encouraging about this time, with Bsal, is that the scientific community figured it out really quickly, and we can learn a lesson from the past.”

Vredenburg is the co-founder of AmphibiaWeb, an online database of information on amphibian biology that receives 7.3 million queries each year. Salamanders are astonishing animals, he said, ranging from species that live 35 feet up in the trees to others that roll into balls and hurl themselves off cliffs to escape predators. The familiar California slender salamanders, found all over Northern California, are one of the groups most threatened by Bsal infection.

“They’re incredibly diverse, they’ve been around for tens of millions of years, and the thought of losing them because of human error, humans moving pathogens around by accident, is just a terrible thought,” Vredenburg said. “And it’s preventable.”  Science Daily  Original web page at Science Daily


Bat disease: Yeast byproduct inhibits white-nose syndrome fungus in lab experiments

A microbe found in caves produces a compound that inhibits Pseudogymnoascus destructans, the fungus that causes white-nose syndrome in bats, researchers report in the journal Mycopathologia. The finding could lead to treatments that kill the fungus while minimizing disruption to cave ecosystems, the researchers say. The yeast Candida albicans produces the compound: trans, trans-farnesol.

Candida species are already present in caves where bats hibernate and have been isolated from the bodies of healthy, hibernating bats, said University of Illinois graduate student Daniel Raudabaugh, who conducted the study with Illinois Natural History Survey mycologist Andrew Miller. This suggests that tt-farnesol is unlikely to harm bats or damage cave ecosystems, Raudabaugh said. “We’re looking for a microbe that’s already associated with bats, that lives in the cave environment and is not a problem for people or other cave life,” he said.

C. albicans is a common resident of human intestines and is found in many other species. The yeast uses tt-farnesol for “quorum-sensing” — at high concentrations, the compound inhibits the growth of fungal projections called mycelia, causing Candida to revert from its invasive form to a more benign, yeast-like state. The compound also disrupts the process by which some bacteria form slimy biofilms that aid in their ability to infect and damage other cells.

“This chemical is known to inhibit other fungi, so we wanted to see if this would inhibit the fungus that causes white-nose syndrome in bats,” Raudabaugh said. “Several million bats have died of white-nose syndrome in the U.S., but European bats appear to survive the infection better,” Miller said. “It is possible that the microbial makeup of European caves plays a role in bat survival there.”

Raudabaugh first tested different concentrations of tt-farnesol against the white-nose fungus and found that, at the right concentrations, it effectively inhibited it. “There are Candida species that already produce this concentration of tt-farnesol, which inhibits P. destructans at biologically produced concentrations,” Raudabaugh said.

Further work must be done to search caves for Candida populations that produce tt-farnesol at effective concentrations. “Inoculating hibernating bats with these microbes to use tt-farnesol as a control agent could increase the bats’ chances of surviving the infection,” Raudabaugh said.

The researchers also discovered that several other Pseudogymnoascus species are less sensitive to tt-farnesol. This suggests the compound could target the white-nose fungus specifically without disrupting other components of the cave ecosystem, Raudabaugh said. “The goal is to preserve as many of the natural species as possible while eradicating P. destructans,” he said. “That is the hope. And so far, it looks promising.” Science Daily Original web page at Science Daily


Treating burn patients: Target gut bacteria?

A study published in PLOS ONE has found that burn patients experience dramatic changes in the 100 trillion bacteria inside the gastrointestinal tract. Loyola University Chicago Health Sciences Division scientists found that in patients who had suffered severe burns, there was a huge increase in Enterobacteriaceae, a family of potentially harmful bacteria. There was a corresponding decrease in beneficial bacteria that normally keep harmful bacteria in check

The findings suggest that burn patients might benefit from treatment with probiotics (live beneficial bacteria). The findings also might apply to other trauma patients, including patients who have suffered traumatic brain injuries, said senior author Mashkoor Choudhry, PhD. In healthy individuals, the gastrointestinal tract contains more than 100 trillion bacteria, called the microbiome, that live symbiotically and provide numerous benefits. If this healthy balance is disrupted, a state called dysbiosis occurs. Dysbiosis has been linked to many conditions, including inflammatory bowel disease, obesity, rheumatoid arthritis and diabetes.

Dr. Choudhry and colleagues examined fecal samples from four severely burned patients who were treated in the Burn Center of Loyola University Medical Center. The samples were taken 5 to 17 days after the burn injuries occurred. The microbiomes of these patients were compared with the microbiomes of a control group of eight patients who had suffered only minor burns.

In the severely burned patients, Enterobacteriaceae accounted for an average of 31.9 percent of bacteria in the gut microbiome. By comparison, Enterobacteriaceae accounted for only 0.5 percent of the microbiome in patients who had suffered minor burns. Enterobacteriaceae is a family of bacteria that includes pathological bacteria such as E. coli and Salmonella.

Dr. Choudhry said such imbalances of bacteria may contribute to sepsis or other infectious complications that cause 75 percent of all deaths in patients with severe burns. The imbalance could compromise the walls of the gastrointestinal tract, enabling harmful bacteria to leak out of the gut and into the bloodstream. Dr. Choudhry is planning further studies to confirm this hypothesis.

A burn or other traumatic injury appears to start a vicious cycle: In response to the injury, the body’s immune system mounts an inflammatory response. This causes an imbalance in the microbiome, further boosting the inflammatory response and triggering an even greater imbalance in the microbiome, said Richard Kennedy, PhD, a co-author of the study. Dr. Choudhry said further research would be needed to determine whether administration of probiotics could restore a healthy microbiome and reduce the risk of sepsis and other infectious complications.  Science Dail  Original web page at Science Daily


New insights into the genetics of drug-resistant fungal infections

A study offers new insights into how virulent fungi adapt through genetic modifications to fight back against the effects of medication designed to block their spread, and how that battle leaves them temporarily weakened.

These insights may provide clues to new ways to treat notoriously difficult-to-cure fungal infections like thrush and vaginitis. A study by a multidisciplinary research team, co-directed by Worcester Polytechnic Institute (WPI), offers new insights into how virulent fungi adapt through genetic modifications to fight back against the effects of medication designed to block their spread, and how that battle leaves them temporarily weakened. These insights may provide clues to new ways to treat notoriously difficult-to-cure fungal infections like thrush and vaginitis.

The team studied patients infected with the fungus Candida albicans (C. albicans), which causes common yeast infections and more serious bloodstream infections, who were being treated with fluconazole, one of the primary anti-fungal drugs now in use. They found that the fungus undergoes 240 genetic changes associated with drug resistance. But those changes come with a cost, they discovered. As it battles to overcome the effects of the drug, the fungus becomes weaker, with a reduction in the traits associated with virulence. The discoveries may point toward new targets for research and the potential to develop new classes of therapeutics for hard-to-treat fungal infections.

The project was co-directed by Reeta Rao, PhD, associate professor of biology and biotechnology at WPI; Dawn Thompson, PhD, and Aviv Regev, PhD, of the Broad Institute of MIT and Harvard; and Judith Berman, PhD, of Tel Aviv University. They report their findings in the paper “The evolution of drug resistance in clinical isolates of Candida albicans,” published by the open-access journal eLife.

“Virtually all humans are colonized with Candida albicans, but in some individuals this benign organism becomes a serious, life-threatening pathogen,” the team wrote. “Here, we used genome sequencing of isolates sampled consecutively from patients that were clinically treated with fluconazole to systematically analyze the genetic dynamics that accompany the appearance of drug resistance during oral candidiasis [infection]. Most of the genes in these clusters are not well characterized and represent new candidates involved (in) drug resistance and adaptation to the host environment.”

In an accompanying eLife “Insight” piece commenting on the importance of the C. albicans drug resistance study, two researchers from the École Polytechnique Fédérale in Lausanne, Switzerland, wrote: “The work provides a global description of the genetic processes underlying drug resistance and adaptation in C. albicans. Of note, all sequencing data have been made publicly available, which is an unprecedented resource for the research community.”

Thrush and vaginitis, common yeast infections caused by C. albicans, typically do not cause serious harm, but can become chronic due to a lack of drugs that can completely clear the pathogen. If a fungal infection spreads to the bloodstream (for example, via catheters or central intravenous lines), it can be deadly. Patients with compromised immune systems or implanted medical devices like pacemakers or prosthetic hips or knees, are also at greater risk for serious systemic fungal infections, which have a mortality rate between 30 and 50 percent.

In the current study, researchers sequenced the DNA and tested samples of C. albicans collected from patients with HIV who also had thrush and were being treated with fluconazole. The “azole” family of drugs do not kill the fungi–they limit growth by disrupting a protein in the yeasts’ outer membrane. In many cases, some C. albicans organisms overcome the effects of fluconazole and continue to cause an infection.

Using next-generation DNA sequencing technology, the team looked for changes at the genetic level in 43 samples of C. albicans collected from the 11 patients over ten months. By sampling fungi from the same patients over time, researchers identified genetic mutations that correlated with the fungi’s evolving ability to overcome the effects of fluconazole in those patients. The results revealed changes in genes associated with the structure of fungi’s outer membrane and the activity of molecular pumps that can eject the drug from the yeast’s cells. Numerous other genetic mutations were found to be prevalent as drug resistance increased, though the functional impact of those changes is not known.

The DNA sequencing and genomic analysis was done at the Broad Institute and Tel Aviv University. At WPI, Rao’s lab tested the fitness and virulence of the C. albicans strains in the 43 samples. Those experiments found an inverse relationship between increased drug resistance and the ability of C. albicans to survive or cause additional infection. “At first that may seem counterintuitive, but it’s actually a logical finding,” Rao said. “It shows there is a fitness cost involved in overcoming the effect of the drug. C. albicans devotes more energy to battling the drug, so it becomes less fit and unable to cause infection until it has figured out how to overcome the effect of the drug.”

Studying that window of vulnerability, when the fungus is weaker and less likely to cause more infection but not fully resistance to the drug, becomes an interesting opportunity to explore, Rao noted. Also, much more work is needed to understand the specific impact of the 240 genetic mutations found to be associated with drug resistance. Furthermore, understanding how C. albicans evades fluconazole may shed light on how some cancer cells develop resistance to current therapies because “the evolution of drug resistance in C. albicans has many parallels with the somatic evolution of cancer cells undergoing chemotherapy or treated with specific inhibitors,” the authors wrote.  Science Daily  Original web page at Science Daily


Urban microbes come out of the shadows

Genomic sequences reveal cities’ teeming masses of bacteria and viruses. Trains are full of more than just people: bacteria stick to seats more effectively than they do to metal poles.

Embedded in the filth and chaos of the world’s great metropolises, amid the people, pigeons, cockroaches and rats, there is a teeming world of bacteria, viruses, fungi and protists that scientists are only now surveying. Microbes are everywhere: on trains, pavements and lifts; in parks, libraries, hospitals and schools. Most are innocuous, some are friendly, and a handful cause death and disease. But the vast majority are unknown.

Researchers described results of early forays into this terra incognita at the Microbes in the City conference on 19 June, hosted by the New York Academy of Sciences and New York University (NYU) on the 40th floor of an antiseptic-looking glass office tower in Manhattan. “We’re really at the infancy of a very interesting scientific endeavour,” said Joel Ackelsberg, a medical epidemiologist for the New York City Department of Health and Mental Hygiene. “Right now, we know very little.”

Researchers are not even sure how to survey this strange landscape. There are competing techniques for detecting, quantifying and keeping track of which microbes are doing what in the built environment, and where. But researchers believe that efforts could lead to new approaches for monitoring bioterrorism, tracking disease outbreaks or assessing the impact of storms and pollution.

Each month, high-throughput techniques allow scientists to sequence roughly 1,000 microbial genomes from samples collected in various environments, said computational biologist Curtis Huttenhower of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts. That is an impressive amount of data, but it is dwarfed by the unfamiliar. Christopher Mason, a computational geneticist at Weill Cornell Medical College in New York City, told the conference how a baseline survey of genetic material from surfaces in the city’s subway system had uncovered DNA from almost 1,700 known taxa, mostly harmless bacteria. But 48% of the genetic material did not match anything yet identified. “Half the world under our fingertips is unknown,” said Mason.

Still, trends are emerging from the global Metagenomics and Metadesign of Subways and Urban Biomes initiative (MetaSUB), which aims to characterize the genetic material found on public-transport systems in 16 world cities to elucidate the microscopic riders that share the commute. Storms leave a mark: months after New York City’s South Ferry Station was flooded in 2012’s Hurricane Sandy, it still harboured DNA from bacteria associated with cold marine environments and fish, Mason said However, most of the bacteria in the subway were harmless Acinetobacter species and others associated with human skin.

In his talk, Huttenhower described a survey of Boston’s transit system that yielded similar flora. “Everything is covered in skin,” he said. He noted that metal poles on the trains, which riders commonly consider hygienically suspect, actually retain much less bacterial biomass than the system’s upholstered seats or plastic hand grips.

Microbiomes in houses tend to match those of the homes’ human inhabitants — and quickly morph after a change in occupancy, said environmental microbiologist Jack Gilbert of Argonne National Laboratory in Illinois. He and his colleagues described results from a survey of ten homes, which found that they become populated with new residents’ microbes within 24 hours.

Rodents are under study, too. White-footed mice (Peromyscus leucopus) in New York City carry more Helicobacter and Atopobium bacteria — associated with stomach ulcers and bacterial vaginosis in humans — than their suburban counterparts, but are totally free of tick-borne pathogens, reported biologist Alyssa Ammazzalorso of the Albert Einstein College of Medicine in New York City. The city’s rats carry a number of bacteria known to cause problems in people, said epidemiologist Ian Lipkin, director of the Center for Infection and Immunity at Columbia University in New York. He and others have found pathogenic Escherichia coli, Clostridium difficile, Salmonella enterica and the Seoul strain of hantavirus, which can be fatal when transmitted to humans (C. Firth et al. mBio 5, e01933-14; 2014).

Sewage samples from New York City’s 14 wastewater-treatment plants turned up a disturbing number of genes for resistance to antibiotics, reported genomicists Susan Joseph and Jane Carlton of NYU’s Center for Genomics and Systems Biology. As a rich human-derived soup spiked with antibiotics, sewage provides an ideal niche for the growth and spread of resistance, Joseph said. Martin Blaser, director of the Human Microbiome Program at the NYU School of Medicine, said that as populations of resistant microbes and their defensive tools become more diverse, the diversity of human-associated microbes in general is declining. He told how he and his colleagues have found that people in the West carry fewer protective bacteria than isolated human groups such as the Yanomami of the Amazon rainforest. “We may have lost as much as half of our diversity already,” says Blaser, “just as we are beginning to realize how important it might be.”

Nature 522, 399–400 (25 June 2015) doi:10.1038/522399a  Nature  Original web page at Nature


Bacteria may help bats to fight deadly fungus

The bats at Marm Kilpatrick’s two Illinois field sites perished right on schedule. The mines sheltered nearly 30,000 bats before white-nose syndrome, a deadly fungal disease, arrived in late 2012. By March 2015, less than 5% remained. Kilpatrick, a disease ecologist at the University of California, Santa Cruz (UCSC), and his colleagues chose the mines because they lay right in the path of the fungus, which has spread from Europe through 26 US states and 5 Canadian provinces since January 2007.

Although researchers are currently helpless to halt the spread of the fungus, there is reason for cautious optimism: treatments could soon be available that will help the bats to keep the infection at bay, for a season at least. The goal, says Chris Cornelison, a micro-biologist at Georgia State University in Atlanta, is to ensure that when researchers find long-term solutions for the disease, “there are still bats to treat”.

The fungus (Pseudogymnoascus destructans) grows on bats while they hibernate in winter, digging into their noses, ears and wings. Animals that survive until spring usually clear the infection as their bodies warm; some species do it year after year. But the pathogen causes other species to repeatedly rouse from hibernation, which burns up fat reserves and can cause the animals to starve to death. Some even flee their roosts in a futile search for food.

“They come out of caves in the winter, and they try to get into people’s homes or churches or schools,” says Jeremy Coleman, national coordinator for white-nose-syndrome research at the US Fish and Wildlife Service in Hadley, Massachusetts. “They’re dead and dying on the ground.”

Kilpatrick and his colleagues have discovered that a bacterium found on bats’ wings may help them to combat infection. In April, the scientists published a paper in PLoS ONE showing that two strains of the bacterium Pseudomonas fluorescens kill white-nose fungus in cell culture (J. R. Hoyt et al. PLoS ONE 10, e0121329; 2015). Last winter, the researchers applied the treatment to bats in the lab. They have not released their results, but Kilpatrick hopes to test the bacteria in the wild soon.

Others are examining whether volatile organic compounds produced by Rhodococcus bacteria, which are found in soils, can kill white-nose spores. During a field trial in Missouri last winter, Cornelison and his colleagues treated bats with such compounds for 48 hours before returning the caged animals to their cave for 4 months to finish hibernating. On 19 May, the researchers released the bats that were free of disease — prompting media coverage of a potential ‘cure’.

Cornelison cautions against such celebration. His team is still analysing the data from the trial, and has not revealed how many bats were treated and released or how the controls fared. And even if this or the bacterial treatments are effective, they will be only short-term solutions. The fungus lingers on cave walls during the summer, and bats do not seem to develop immunity to it — so researchers would need to treat the animals every year to keep them from getting sick.

Long-lasting solutions remain elusive. Some scientists hope to develop a vaccine, but have yet to work out how to trigger the animals’ immune systems to destroy the pathogen, says Ken Field, an ecoimmunologist at Bucknell University in Lewisburg, Pennsylvania. Bats naturally produce antibodies to the fungus, but there is no evidence that these can help them to survive.

Other researchers are promoting a more radical long-term solution: altering airflow in mines where bats hibernate to make the sites less hospitable to the white-nose fungus. Places where bats survive infection tend to be relatively cool and dry. By opening new routes to the outside, researchers could cool and dehumidify the air in mines that are too warm and wet.

There is a chance that manipulating airflow could drive bats to abandon the habitat, says Kate Langwig, an ecologist at the UCSC. But she argues that it is worth a try, because at some sites the white-nose fungus kills about 90% of the bats present. In the first 5 years that it was present in the United States, the pathogen claimed more than 5.5 million animals.

In the meantime, the United States and Canada are developing and implementing strategies to coordinate work by scientists and by local and national governments — ranging from laboratory and field studies to efforts to prevent people from inadvertently spreading the fungus to pristine caves.

The plight of the bats is “stark — it’s demoralizing”, says Winifred Frick, an ecologist at the UCSC. “But I have hope in terms of the amount of creative energy and sense of dedication that people are putting forth on this problem. If there are solutions, we will find them.”

Nature 522, 400–401 (25 June 2015) doi:10.1038/522400a  Nature  Original web page at Nature


Researchers engineer E. coli to produce new forms of popular antibiotic

Like a dairy farmer tending to a herd of cows to produce milk, researchers are tending to colonies of the bacteria Escherichia coli (E. coli) to produce new forms of antibiotics — including three that show promise in fighting drug-resistant bacteria. The research, which is published May 29  in the journal Science Advances, was led by Blaine A. Pfeifer, an associate professor of chemical and biological engineering in the University at Buffalo School of Engineering and Applied Sciences. His team included first author Guojian Zhang, Yi Li and Lei Fang, all in the Department of Chemical and Biological Engineering.

For more than a decade, Pfeifer has been studying how to engineer E. coli to generate new varieties of erythromycin, a popular antibiotic. In the new study, he and colleagues report that they have done this successfully, harnessing E. coli to synthesize dozens of new forms of the drug that have a slightly different structure from existing versions. Three of these new varieties of erythromycin successfully killed bacteria of the species Bacillus subtilis that were resistant to the original form of erythromycin used clinically

‘We’re focused on trying to come up with new antibiotics that can overcome antibiotic resistance, and we see this as an important step forward,’ said Pfeifer, Ph.D. ‘We have not only created new analogs of erythromycin, but also developed a platform for using E. coli to produce the drug,’ he said. ‘This opens the door for additional engineering possibilities in the future; it could lead to even more new forms of the drug.’ The study is especially important with antibiotic resistance on the rise. Erythromycin is used to treat a variety of illnesses, from pneumonia and whooping cough to skin and urinary tract infections.

Getting E. coli to produce new antibiotics has been something of a holy grail for researchers in the field. That’s because E. coli grows rapidly, which speeds experimental steps and aids efforts to develop and scale up production of drugs. The species also accepts new genes relatively easily, making it a prime candidate for engineering. While news reports often focus on the dangers of E. coli, most types of this bacteria are actually harmless, including those used by Pfeifer’s team in the lab.

Over the past 11 years, Pfeifer’s research has focused on manipulating E. coli so that the organism produces all of the materials necessary for creating erythromycin. You can think of this like stocking a factory with all the necessary parts and equipment for building a car or a plane. With that phase of the research complete, Pfeifer has turned to the next goal: Tweaking the way his engineered E. coli produce erythromycin so that the drug they make is slightly different than versions used in hospitals today.

The process of creating erythromycin begins with three basic building blocks called metabolic precursors — chemical compounds that are combined and manipulated through an assembly line-like process to form the final product, erythromycin. To build new varieties of erythromycin with a slightly different shape, scientists can theoretically target any part of this assembly line, using various techniques to affix parts with structures that deviate slightly from the originals. (On an assembly line for cars, this would be akin to screwing on a door handle with a slightly different shape.)

In the new study, Pfeifer’s team focused on a step in the building process that had previously received little attention from researchers, a step near the end. The researchers focused on using enzymes to attach 16 different shapes of sugar molecules to a molecule called 6-deoxyerythronolide B. Every one of these sugar molecules was successfully adhered, leading, at the end of the assembly line, to more than 40 new analogs of erythromycin — three of which showed an ability to fight erythromycin-resistant bacteria in lab experiments. ‘The system we’ve created is surprisingly flexible, and that’s one of the great things about it,’ Pfeifer said. ‘We have established a platform for using E. coli to produce erythromycin, and now that we’ve got it, we can start altering it in new ways.’  Science Daily  Original web page at Science Daily


* Swine farming a risk factor for drug-resistant staph infections, study finds

Swine farmers are more likely to carry multidrug-resistant Staphylococcus aureus (S. aureus or “staph”) than people without current swine exposure, according to a study conducted by a team of researchers from the University of Iowa, Kent State University, and the National Cancer Institute. The study, published online in the journal Clinical Infectious Diseases, is the largest prospective examination of S. aureus infection in a group of livestock workers worldwide, and the first such study in the United States.

S.aureus is a type of bacteria commonly found on the skin as well as in the noses and throats of people and animals. About 30 percent of the U.S. population carries these bacteria, which can cause a range of skin and soft tissue infections. Although most infections are minor, S. aureus can sometimes cause serious infections. Increasingly, drug-resistant strains of S. aureus are emerging, including methicillin-resistant (MRSA), tetracycline-resistant (TRSA), or multidrug-resistant (MDRSA) strains. And while previous studies have shown that certain strains of S. aureus are often associated with swine, cattle, and poultry exposure, little is known about livestock-associated staph carriage and infection in the United States.

The study authors note the research helps keep farmers safe by raising awareness about a potential health issue in swine operations. S. aureus does not present an economic concern for swine farmers since pigs generally are unaffected by staph infections.

S. aureus does not typically make pigs sick, but they can act as carriers and transmit the bacterium to farmers,” says Tara Smith, corresponding author on the study. “While carriage of S. aureus isn’t itself harmful, individuals who harbor the bacterium in their nose, throat, or on their skin are at risk of developing an active staph infection, and they can also pass the bacterium to other family or community members. Individuals who may be immunocompromised, or have existing conditions such as diabetes, are especially at risk from staph infections.”

For the study, the researchers followed a group of 1,342 Iowans, including individuals with livestock contact and a community-based comparison group, for 17 months. The participants were recruited from 53 of Iowa’s 99 counties and lived in rural areas or small towns. Nose and throat swabs were collected from participants at the beginning of the study to determine if they carried S. aureus. Participants who experienced skin infections during the study period also were assessed for S. aureus. Overall, 26 percent of the participants carried S. aureus. However, the investigators found that farmers with livestock exposure, particularly swine exposure, were more likely to carry MDRSA, TRSA, and livestock-associated S. aureus than those who weren’t exposed to livestock.

“Current swine workers were six times more likely to carry multidrug-resistant S. aureus than those study participants without current swine exposure,” says Smith. The study is based on research that Smith, currently an associate professor at Kent State University, conducted while she was a faculty member at the UI College of Public Health. “Swine workers are also at risk of becoming infected with these organisms,” Smith adds. “One hundred and three potential S. aureus infections were reported, and included infections with livestock-associated strains of this bacterium.” There currently is no method to prevent or eliminate carriage of S. aureus in animals or their human caretakers, meaning constant re-exposure and possibly transmission can occur between livestock and farm workers. Those workers can then pass staph to their family or community members.

“Iowa ranks third nationally in overall livestock production and first in swine production,” notes Smith. “Transmission of staph between pigs and farmers and into the broader community could complicate efforts to control S. aureus transmission statewide, and have effects nationally due to the travel of pigs and people carrying these bacteria.  Science Daily  Original web page at Science Daily


* Programming DNA to reverse antibiotic resistance in bacteria

New research introduces a promising new tool to combat the rapid, extensive spread of antibiotic resistance around the world. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, if ultimately applied to pathogens on hospital surfaces or medical personnel’s hands, could turn the tide on untreatable, often lethal bacterial infections. At its annual assembly in Geneva last week, the World Health Organization approved a radical and far-reaching plan to slow the rapid, extensive spread of antibiotic resistance around the world. The plan hopes to curb the rise caused by an unchecked use of antibiotics and lack of new antibiotics on the market.

New Tel Aviv University research published in PNAS introduces a promising new tool: a two-pronged system to combat this dangerous situation. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU’s Sackler Faculty of Medicine, is based on bacterial viruses called phages, which transfer “edited” DNA into resistant bacteria to kill off resistant strains and make others more sensitive to antibiotics.

According to the researchers, the system, if ultimately applied to pathogens on hospital surfaces or medical personnel’s hands, could turn the tide on untreatable, often lethal bacterial infections. “Since there are only a few pathogens in hospitals that cause most of the antibiotic-resistance infections, we wish to specifically design appropriate sensitization treatments for each one of them,” Prof. Qimron says. “We will have to choose suitable combinations of DNA-delivering phages that would deliver the DNA into pathogens, and the suitable combination of ‘killing’ phages that could select the re-sensitized pathogens.”

“Antibiotic-resistant pathogens constitute an increasing threat because antibiotics are designed to select resistant pathogens over sensitive ones,” Prof. Qimron says. “The injected DNA does two things: It eliminates the genes that cause resistance to antibiotics, and it confers protection against lethal phages. “We managed to devise a way to restore antibiotic sensitivity to drug-resistant bacteria, and also prevent the transfer of genes that create that resistance among bacteria,” he continues.

Earlier research by Prof. Qimron revealed that bacteria could be sensitized to certain antibiotics — and that specific chemical agents could “choose” those bacteria more susceptible to antibiotics. His strategy harnesses the CRISPR-Cas system — a bacterial DNA-reprogramming system Prof. Qimron pioneered — as a tool to expand on established principles.

According to the researchers, “selective pressure” exerted by antibiotics renders most bacteria resistant to them — hence the epidemic of lethal resistant infections in hospitals. No counter-selection pressure for sensitization of antibiotics is currently available. Prof. Qimron’s strategy actually combats this pressure — selecting for the population of pathogens exhibiting antibiotic sensitivity.

“We believe that this strategy, in addition to disinfection, could significantly render infections once again treatable by antibiotics,” said Prof. Qimron. Prof. Qimron and his team are now poised to apply the CRISPR/phage system on pseudomonas aeruginosa — one of the world’s most prevalent antibiotic-resistant pathogens involved in hospital-acquired infections — and to test whether bacterial sensitization works in a more complex microbial environment: the mouse cage.  Science Daily  Original web page at Science Dail


New strategies for stopping the spread of Staph and MRSA

Staphylococcus aureus — better known as Staph — is a common inhabitant of the human nose, and people who carry it are at increased risk for dangerous Staph infections. However, it may be possible to exclude these unwelcome guests using other more benign bacteria, according to a new study. The study, published in the AAAS journal Science Advances, suggests that a person’s environment is more important than their genes in determining the bacteria that inhabit their noses.

The study also suggests that some common nasal bacteria may prevent Staph colonization. “This study is important because it suggests that the bacteria in the nose are not defined by our genes and that we may be able to introduce good bacteria to knock out bad bugs like Staph.” said Lance B. Price, Ph.D., the Director of TGen’s Center for Microbiomics and Human Health and a Professor of Environmental and Occupational Health at the Milken Institute SPH. “Using probiotics to promote gut health has become common in our culture. Now we’re looking to use these same strategies to prevent the spread of superbugs.”

The multi-center research team looked at data taken from 46 identical twins and 43 fraternal twins in the Danish Twin Registry, one of the oldest registries of twins in the world. “We showed that there is no genetically inherent cause for specific bacteria in the nasal microbiome,” said senior author Dr. Paal Skytt Andersen. Dr. Andersen is head of the Laboratory for Microbial Pathogenesis and Host Susceptibility in the Department of Microbiology and Infection Control at the Statens Serum Institut and an Adjunct Professor at the University of Copenhagen.

The so-called nasal microbiome is the collection of microbes living deep within the nasal cavity. This research might ultimately lead to interventions that could route Staph from the nose and thus prevent dangerous infections, including those caused by antibiotic resistant Staph, the authors say. Studies suggest drug-resistant Staph infections kill more than 18,000 people in the United States every year.

The researchers also looked for possible gender differences and found that contrary to past studies that showed that men are at higher risk for Staph nasal colonization — this study, using DNA sequencing, found that there is no difference between men and woman in the likelihood of nasal colonization by Staph.

“This was a surprising finding. I felt like I was one of the MythBusters guys. For years, most scientists agreed that men were more likely to be colonized by Staph than women. But now we see that that was probably just an artifact of using old methods and that men just tend to have more bacteria in their noses, which makes them easier to culture,” said Dr. Cindy Liu, a Pathology resident at Johns Hopkins School of Medicine and the study’s lead author.

Importantly, the study found evidence that other types of organisms can disrupt Staph. A prime example is Corynebacterium, a mostly harmless bacterium that is commonly found on the skin. The study found that having high amounts of Corynebacterium in the nose was predictive of having low amounts of Staph and vise versa. “We believe this study provides the early evidence that the introduction of probiotics could work to prevent or knock out Staph from the nose,” said Dr. Liu.  Science Daily  Original web page at Science Daily


* European rabbits as reservoir for Coxiella burnetii

We studied the role of European rabbits (Oryctolagus cuniculus) as a reservoir for Coxiella burnetii in the Iberian region. High individual and population seroprevalences observed in wild and farmed rabbits, evidence of systemic infections, and vaginal shedding support the reservoir role of the European rabbit for C. burnetii.

Wildlife play a major role in the maintenance and transmission of multihost pathogens. Understanding the role of host species involved in multihost zoonotic pathogen maintenance and transmission is essential to prevent disease caused by these pathogens. Coxiella burnetii, which is the cause of Q fever, is a zoonotic pathogen that infects multiple hosts. The implication of wildlife in the life cycle of C. burnetii has been reported worldwide, and wildlife might act as a source for humans infections.

European rabbits (Oryctolagus cuniculus) are native to the Iberian Peninsula and have been introduced into Australia, New Zealand, Chile, and Argentina. Domestic varieties of European rabbits are farmed worldwide. Specific ecologic traits (high density, gregarious behavior, high reproductive rate) suggest that these rabbits might become a major reservoir of zoonotic pathogens. However, whether C. burnetii can infect, replicate in, and be shed by European rabbits and contaminate the environment is not known. In this study, we investigated the role of these rabbits in a region to which Q fever is endemic.

Read more:  Emerging Infectious Diseases  Original web page at Emerging Infectious Disease


* New chip makes testing for antibiotic-resistant bacteria faster, easier

We live in fear of ‘superbugs’: infectious bacteria that don’t respond to treatment by antibiotics, and can turn a routine hospital stay into a nightmare. Now, researchers have designed a diagnostic chip to reduce testing time of antibiotics from days to one hour, allowing doctors to pick the right antibiotic the first time. Schematic of the antibiotic susceptibility testing device. The bacteria are cultured in miniature chambers, each of which contains a filter for bacterial capture and electrodes for readout of bacterial metabolism.

A 2015 Health Canada report ( estimates that superbugs have already cost Canadians $1 billion, and are a “serious and growing issue.” Each year two million people in the U.S. contract antibiotic-resistant infections, and at least 23,000 people die as a direct result. But tests for antibiotic resistance can take up to three days to come back from the lab, hindering doctors’ ability to treat bacterial infections quickly. Now Ph.D. researcher Justin Besant and his team at the University of Toronto have designed a small and simple chip to test for antibiotic resistance in just one hour, giving doctors a shot at picking the most effective antibiotic to treat potentially deadly infections. Their work was published this week in the international journal Lab on a Chip.

Resistant bacteria arise in part because of imprecise use of antibiotics — when a patient comes down with an infection, the doctor wants to treat it as quickly as possible. Samples of the infectious bacteria are sent to the lab for testing, but results can take two to three days. In the meantime, the doctor prescribes her patient a broad-spectrum antibiotic. Sometimes the one-size-fits-all antibiotic works and sometimes it doesn’t, and when the tests come back days later, the doctor can prescribe a specific antibiotic more likely to kill the bacteria. “Guessing can lead to resistance to these broad-spectrum antibiotics, and in the case of serious infections, to much worse outcomes for the patient,” says Besant. “We wanted to determine whether bacteria are susceptible to a particular antibiotic, on a timescale of hours, not days.”

The problem with most current tests is the time it takes for bacteria to reproduce to detectable levels. Besant and his team, including his supervisor Professor Shana Kelley of the Institute for Biomaterials & Biomedical Engineering and the Faculties of Pharmacy and Medicine, and Professor Ted Sargent of The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, drew on their collective expertise in electrical and biomedical engineering to design a chip that concentrates bacteria in a miniscule space–just two nanolitres in volume–in order to increase the effective concentration of the starting sample

They achieve this high concentration by ‘flowing’ the sample, containing the bacteria to be tested, through microfluidic wells patterned onto a glass chip. At the bottom of each well a filter, composed of a lattice of tiny microbeads, catches bacteria as the sample flows through. The bacteria accumulate in the nano-sized well, where they’re trapped with the antibiotic and a signal molecule called resazurin.

Living bacteria metabolize resazurin into a form called resorufin, changing its electrochemical signature. If the bacteria are effectively killed by the antibiotic, they stop metabolizing resazurin and the electrochemical signature in the sample stays the same. If they are antibiotic-resistant, they continue to metabolize resazurin into resorufin, altering its electrochemical signature. Electrodes built directly into the chip detect the change in current as resazurin changes to resorcin. “This gives us two advantages,” says Besant. “One, we have a lot of bacteria in a very small space, so our effective starting concentration is much higher. And two, as the bacteria multiply and convert the resazurin molecule, it’s effectively stuck in this nanolitre droplet–it can’t diffuse away into the solution, so it can accumulate more rapidly to detectable levels.” “Our approach is the first to combine this method of increasing sample concentration with a straightforward electrochemical readout,” says Professor Sargent. “We see this as an effective tool for faster diagnosis and treatment of commonplace bacterial infections.”

Rapid alternatives to existing antibiotic resistance tests rely on fluorescence detection, requiring expensive and bulky fluorescence microscopes to see the result. “The electronics for our electrochemical readout can easily fit in a very small benchtop instrument, and this is something you could see in a doctor’s office, for example,” says Besant. “The next step would be to create a device that would allow you to test many different antibiotics at many different concentrations, but we’re not there yet.” Science Daily  Original web page at Science Daily


Vulnerability found in some drug-resistant bacteria

A new study analyzing the physical dynamics of all currently mapped structures in an important group of antibiotic-destroying enzymes has found a common structural feature: the physical coordination of a set of flexible components. The apparently universal nature of this complex structural dynamic implies that it is critical to the antibiotic destroying properties of the enzyme and points to the possibility of finding a way to chemically disable the enzymes and bacterial antibiotic resistance, experts say. Using a complex modeling program that helps analyze the physical dynamics of large, structurally complex protein molecules, a research team has made progress towards finding a weak spot in the architecture of a group of enzymes that are essential to antibiotic resistance in a number of bacteria.

In an article published in PLOS ONE, University of North Carolina at Charlotte senior biology major Jenna R. Brown and her faculty mentor, UNC Charlotte professor of bioinformatics and genomics Dennis R. Livesay, present an analysis of the four currently known protein structures of the class C beta-lactamase enzymes — molecular machines that have evolved to allow bacteria to dismantle a variety of antibiotic molecules, including third generation cephalosporins.

The researchers find that all four molecules are remarkably similar in having a rigid protein superstructure, but with three “flexible” structural elements at the active site — the part of the enzyme that acts on the antibiotic. The analysis shows that the flexible structures are “cooperatively correlated” in their motions — the movements of the molecular segments are linked and the linkage is similar in all four molecules analyzed.

The researchers say that the unusual close similarity of the dynamical properties — the way the coupled dynamics within the active site loops is been preserved by the evolutionary process in four different bacterial groups — and the fact that the conserved correlated flexibility happens at the active site implies that this specific structural feature is critical to its advanced antibacterial properties.

“From an evolutionary perspective, this is really cool,” Livesay said. “Here’s a protein that has a very intense set of evolutionary pressures on it, making these couplings critical and not allowing them to vary. We’ve never seen that before. Typically these couplings are quite variable, even when they are otherwise closely related enzymes.” “Clearly this result is important because it is at the active site, because it is evolutionarily conserved, and because we have never seen this degree of conservation in any other system before,” Livesay noted.

The analysis was done using the Distance Constraint Model (DCM), a protein analysis program developed by Livesay and UNC Charlotte biophysicist Donald Jacobs that allows relatively detailed but also relatively streamlined comparison of the properties and behaviors of complex protein structures based on their sequence of amino acids. The DCM’s efficient but accurate structural analysis allowed the researchers to make complex structural comparisons between many different (but related) protein molecules in realistic computing timescales that would be inaccessible by traditional methods. The DCM allows researchers to quickly and accurately pinpoint specific differences in dynamical properties between the structures, such as differing amounts of rigidity/flexibility in specific parts of the protein’s complex structure.  Science Daily  Original web page at Science Daily


Panda guts not suited to digesting bamboo

Bear’s microbiome shows poor evolutionary adaptation to the fibrous food. Pandas make quick work of bamboo, using their powerful jaws to peel back the plant’s tough outer stalk and reach the tender heart. But new research suggests that microorganisms in the bear’s gut are not quite as adept at breaking down the species’ primary food source. The study, published on 19 May in mBio, reveals that the gut bacteria of giant pandas (Ailuropoda melanoleuca) have not evolved to efficiently break down cellulose, a hard-to-digest fibre found in plant walls. The bears’ gut microbiome is more closely related to that of carnivores, rather than other herbivores.

Ancient giant pandas, which were originally omnivorous, began incorporating bamboo into their diet at least 7 million years ago, and switched to eating bamboo exclusively 2.4 million to 2 million years ago. The bears evolved strong jaws and a ‘pseudothumb’ to help them to consume the plant. But unlike other herbivores, they did not develop an elongated digestive tract or enzymes to help break down tough plant parts.  “It is really interesting when you have a lineage that does something really differently from its relatives in terms of its food and what happens with the microbiome in relation to that change,” says Jonathan Eisen, a microbial ecologist at the University of California, Davis.

To study the panda’s gut microbiome, researchers in China sequenced ribosomal RNA in faeces collected from 45 pandas of different ages over the course of a year. The scientists compared the microbes found in the panda faeces to those in the faeces of other mammals, such as bears, lions, horses and kangaroos. The team found little diversity in the microorganisms that live in panda guts, and none of the cellulose-degrading bacteria typically seen in other plant-eaters. Instead, the pandas’ guts were dominated by Escherichia, Shigella and Streptococcus bacteria, which are normally found in carnivores.

That surprises David Sela, a genomic biologist at the University of Massachusetts Amherst. Typically, he says, a major change in an animal’s diet, such as the panda’s shift to bamboo millions of years ago, leads to changes in microbiota composition and function. Eisen says that some of the microbes in the panda gut might still be highly efficient at breaking down cellulose. He argues that the study’s authors examined only microbial composition, not function — and microbes can change function rapidly, making it hard to predict how they perform solely on the basis of the genera of bacteria present. A 2011 study found evidence that Clostridium bacteria in panda guts contained genes that resembled those known to produce enzymes that break cellulose down into simpler sugars. “I’m not convinced at all that there’s any limitation to the cellulolytic activity in this system based upon the data they have,” Eisen says of the new study. The researchers say that the most important question of the study is whether the panda’s carnivore-like microbial structure can still effectively utilize cellulose. More work will help to provide a complete picture.

Nature doi:10.1038/nature.2015.17582  Nature  Original web page at Nature


Horizontal gene transfer in E. coli

Escherichia coli O104 is an emergent disease-causing bacterium various strains of which are becoming increasingly well known and troublesome. The pathogen causes bloody diarrhea as well as and potentially fatal kidney damage, hemolytic uremic syndrome. Infection is usually through inadvertent ingestion of contaminated and incompletely cooked food or other materials, such as animals feces.

Escherichia coli is a so-called gram negative bacterium, commonly found in the intestine of humans and other mammals. Entero-hemorrhagic strains including O157, O26, O103 and O111 and specifically the sub-strain O157:H7 is an important cause of food borne illness in North America, the UK and Japan. One particular strain, highlighted by Indian researchers in the International Journal of Bioinformatics Research and Applications, O104:H4, causes serious complications and has developed significant multiple-drug resistance to antibiotics. Moreover, it has acquired genes through horizontal transfer from other strains that make it even more virulent than others.

The team from Madurai Kamaraj University in Madurai, Tamil Nadu, working with colleagues at Genotypic Technology Pvt Ltd in Karnataka, have used the tools of computational molecular biology to identify 38 such horizontal gene transfer elements, prophage elements. These elements the team explains are genetic weapons that protect the bacteria from antibiotics and have been acquired from viruses, known as bacteriophages, that usually infect bacteria. More than a quarter of the genome of this strain of E. coli comprises prophage elements, the team explains. These elements are also involved in the production of lethal compounds such as Shiga toxin, which give rise to many of the symptoms of infection. As such, they might represent new diagnostic markers or even targets for the development of novel antibiotics that circumvent the protective measures acquired by the bacteria.  Science Daily  Original web page at Science Daily


Increasing evidence points to inflammation as source of nervous system manifestations of Lyme disease

About 15% of patients with Lyme disease develop peripheral and central nervous system involvement, often accompanied by debilitating and painful symptoms. New research indicates that inflammation plays a causal role in the array of neurologic changes associated with Lyme disease, according to a study published in The American Journal of Pathology. The investigators at the Tulane National Primate Research Center and Louisiana State University Health Sciences Center also showed that the anti-inflammatory drug dexamethasone prevents many of these reactions. “These results suggest that inflammation has a causal role in the pathogenesis of acute Lyme neuroborreliosis,” explained Mario T. Philipp, PhD, Professor of Microbiology and Immunology and chair of the Division of Bacteriology and Parasitology at Tulane National Primate Research Center (Covington, LA).

Lyme disease in humans results from the bite of a tick infected with the spirochete Borrelia burgdorferi (Bb). As Bb disseminates throughout the body, it can cause arthritis, carditis, and neurologic deficits. When the nervous system is involved, it is called Lyme neuroborreliosis (LNB). Clinical symptoms of LNB of the peripheral nervous system may include facial nerve palsy, neurogenic pain radiating along the back into the legs and feet, limb pain, sensory loss, or muscle weakness. Central nervous system involvement can manifest as headache, fatigue, memory loss, learning disability, depression, meningitis, and encephalopathy.

To understand further the neuropathologic effects of Bb infection, researchers infected 12 rhesus macaques with live B. burgdorferi; two animals were left uninfected as controls. Of the 12 Bb-inoculated animals, four were treated with the anti-inflammatory steroid dexamethasone, four with the non-steroidal anti-inflammatory drug (NSAID) meloxicam, and four remained untreated. Half of each group was studied for eight weeks postinoculation and the other half for 14 weeks

The researchers examined the role of inflammation in the nervous systems of Bb-infected animals. Significantly elevated levels of the inflammatory mediators interleukin-6 (IL-6), IL-8, CCL2, and CXCL13 were observed, as well as pleocytosis (increased cell counts, primarily white blood cells) in the cerebrospinal fluid of all infected animals — except in those treated with dexamethasone. “Chemokines such as IL-8 and CCL2 are known to mediate the influx of immune cells in the central nervous system compartment during bacterial meningitis, and CXCL13 is the major determinant of B cell recruitment into the cerebrospinal fluid during neuroinflammation,” explained Dr. Philipp.

Infection with Bb led to many histopathologic findings in infected animals not treated with dexamethasone, such as leptomeningitis, vasculitis, focal inflammation in the brain and spinal cord, and necrotizing focal neurodegeneration and demyelination in the cervical spinal cord. Evaluation of the dorsal root ganglia showed inflammation with neurodegeneration, along with significant apoptosis of neuronal and satellite glial cells (which surround sensory neurons), in all infected animals with the exception of those treated with dexamethasone. Researchers were able to quantify the protective effect of dexamethasone treatment in protecting both satellite glial cell and neuronal apoptosis; in contrast, meloxicam treatment was only effective in protecting against satellite glial cell apoptosis and only after prolonged administration.

The dorsal roots of animals infected with live Bb (but not treated with dexamethasone) showed the presence of abundant lymphocytes and monocytes. Interestingly, reactions near the injection sites were histologically different from the more diffuse inflammation found along the spinal cord. The pathology found in the dorsal root ganglia and sensory nerves may explain the localized pain and motor deficits that Lyme disease patients experience close to the origin of the tick bite. Some patients with Lyme disease also show evidence of demyelinating neuropathy and slowing nerve conduction. Nerve conduction studies in motor and sensory nerves of the macaques showed that the Bb infection resulted in specific electrophysiological abnormalities (increased F wave latencies and chronodispersion) that could be prevented with dexamethasone

Although antibiotics are the standard and necessary first-line treatment for Lyme disease, the results show the potential therapeutic impact of anti-inflammatory or immune-modulatory agents for Lyme-related neuroborreliosis. Most of the neuropathological changes produced by Bb infection were prevented by dexamethasone, a broad-spectrum steroidal anti-inflammatory drug, whereas the non-steroidal anti-inflammatory drug meloxicam was generally ineffective or only partially effective. Analyses of the differences in the mechanisms of action of both drugs may provide a blueprint for the development of new adjuvant treatments for LNB

“Importantly, we found necrotizing myelitis and degeneration in the spinal cord, neurodegeneration in the dorsal root ganglia, and demyelination in the nerve roots only when lymphocytic inflammatory lesions were also observed in both the central nervous system and peripheral nervous system,” stated Dr. Philipp. “Our results suggest that ongoing cytokine activation in the nervous system can contribute to the persistent symptoms of fatigue, pain, and cognitive dysfunction that patients sometimes experience despite having been treated for Lyme disease.”  Science Daily  Original web page at Science Daily


Stomach ulcers in cattle: Bacteria play only a minor role

Scientists at the University of Veterinary Medicine Vienna investigated whether stomach ulcers in cattle are related to the presence of certain bacteria. For their study, they analysed bacteria present in healthy and ulcerated cattle stomachs and found very few differences in microbial diversity. Bacteria therefore appear to play a minor role in the development of ulcers. The microbial diversity present in the stomachs of cattle has now for the first time been published in the journal Veterinary Microbiology.

Gastritis and stomach ulcers in humans are often caused by the bacterium Helicobacter pylori. But other factors, such as stress and nutrition, also play a role in stomach health. In cattle the weather and husbandry in general play an additional role. The etiological role of bacteria in abomasal ulcers was investigated by veterinarian Alexandra Hund of the Clinical Unit of Ruminant Medicine together with microbiologist Stephan Schmitz-Esser of the Institute for Milk Hygiene. “The abomasum is the last of the four stomach compartments in cattle. The three other compartments, the rumen, the reticulum and the omasum, serve to predigest the food. The abomasum is the actual stomach and is similar in anatomy and function to the human stomach. Painful gastritis and ulcers can occur in the abomasa of cattle, potentially weakening the animals, leading to perforations of the stomach and possibly even to cases of death,” first author Alexandra Hund explains.

Microbiologist Schmitz-Esser analysed stomach samples from slaughter cattle. Around half of the samples were taken from healthy cattle, the other half from cattle with low-grade abomasal ulcers. “Very sick animals are barred from slaughter,” says Alexandra Hund. The researchers isolated and sequenced the bacterial DNA from the stomach samples. The DNA sequences were then used to determine the type of bacteria present. “The most common were species of Helicobacter, Acetobacter, Lactobacillus and new strains of Mycoplasma. The bacterium Helicobacter pylori, commonly found in humans, was not present at all. We nearly saw the same bacterial composition in healthy and ulcerated animals, which suggests that bacteria only play a minor role in the etiology of abomasal ulcers,” says Schmitz-Esser. “However, this is something we would like to underpin in future studies.”

Calf stomachs contain a relatively immature microbial biomass. This means that bacterial diversity must still develop. The primary bacteria found in calf stomachs were beneficial lactic acid bacteria. These bacteria enter the stomachs of calves through the milk that forms their main source of nutrition. “Due to the very subtle symptoms of abomasal ulcers, they are very difficult to diagnose for non-experts. The abomasum is the last of the four stomach compartments and therefore not accessible to gastroscopy. We are currently working on a method for the early and rapid diagnosis of those ulcers. In any case, keeping cattle stress-free is one way of preventing stomach ulcers,” Alexandra Hund recommends.  Science Daily  Original web page at Science Daily


Bacterial flora of remote tribespeople carries antibiotic resistance genes

The research stems from the 2009 discovery of a tribe of Yanomami Amerindians in a remote mountainous area in southern Venezuela. Largely because the tribe had been isolated from other societies for more than 11,000 years, its members were found to have among the most diverse collections of bacteria recorded in humans. Within that plethora of bacteria, though, the researchers have identified genes wired to resist antibiotics.

The study, published April 17 in Science Advances, reports that the microbial populations on the skin and in the mouths and intestines of the Yanomami tribespeople were much more diverse than those found in people from the United States and Europe. The multicenter research was conducted by scientists at New York University School of Medicine, Washington University School of Medicine in St. Louis, the Venezuelan Institute of Scientific Research and other institutions. “This was an ideal opportunity to study how the connections between microbes and humans evolve when free of modern society’s influences,” said Gautam Dantas, PhD, associate professor of pathology and immunology at Washington University and one of the study’s authors. “Such influences include international travel and exposure to antibiotics.”

Intriguingly, in Dantas’ lab, graduate student Erica Pehrsson searched for and found antibiotic resistance genes in bacteria on the skin and in the mouths and intestines of tribe members long isolated from such outside influences. “These people had no exposure to modern antibiotics; their only potential intake of antibiotics could be through the accidental ingestion of soil bacteria that make naturally occurring versions of these drugs,” Pehrsson said. “Yet we were able to identify several genes in bacteria from their fecal and oral samples that deactivate natural, semi-synthetic and synthetic drugs.” Thousands of years before people began using antibiotics to fight infections, soil bacteria began producing natural antibiotics to kill competitors. Similarly, microbes evolved defenses to protect themselves from the antibiotics their bacterial competitors would make, likely by acquiring resistance genes from the producers themselves through a process known as horizontal gene transfer.

In recent years, the abundance of antibiotics in medicine and agriculture has accelerated this process, stimulating the development and spread of genes that help bacteria survive exposure to antibiotics. Consequently, strains of human disease that are much harder to treat have emerged. “We have already run out of drugs to treat some types of multidrug-resistant infections, many of which can be lethal, raising the bleak prospect of a post-antibiotic era,” Dantas said. Scientists don’t really know whether the diversity of specific bacteria improves or harms health, Dantas said, but added that the microbiomes of people in industrialized countries are about 40 percent less diverse than what was found in the tribespeople never exposed to antibiotics. “Our results bolster a growing body of data suggesting a link between, on one hand, decreased bacterial diversity, industrialized diets and modern antibiotics, and on the other, immunological and metabolic diseases — such as obesity, asthma, allergies and diabetes, which have dramatically increased since the 1970s,” said Maria Dominguez-Bello, PhD, associate professor of medicine at New York University Langone Medical Center and senior author of the study. “We believe there is something occurring in the environment during the past 30 years that has been driving these diseases, and we think the microbiome could be involved.”

Dominguez-Bello said the research suggests a link between modern antibiotics, diets in industrialized parts of the world and a greatly reduced diversity in the human microbiome — the trillions of bacteria that live in and on the body and that are increasingly being recognized as vital to good health. The vast majority of human microbiome studies have focused on Western populations, so access to people unexposed to antibiotics and processed diets may shed light on how the human microbiome has changed in response to modern culture, and may point to therapies that can address disease-causing imbalances in the microbiome. In the current study, when the researchers exposed cultured bacterial species from the tribe to 23 different antibiotics, the drugs were able to kill all of the bacteria. However, the scientists suspected that these susceptible bacteria might carry silent antibiotic resistance genes that could be activated upon exposure to antibiotics. They tested for such activation, and the tests confirmed their suspicions. The bacterial samples contained many antibiotic resistance genes that can fend off many modern antibiotics. These genes may turn on in response to antibiotic exposure.

“However, we know that easily cultured bacteria represent less than 1 percent of the human microbiota, and we wanted to know more about potential resistance in the uncultured majority of microbes,” Dantas said. So the researchers applied the same method, called functional metagenomics, to identify functional antibiotic resistance genes from Yanomami fecal and oral samples without any prior culturing. From that experiment they were able to identify nearly 30 additional resistance genes. Many of these genes deactivated natural antibiotics, but the scientists also found multiple genes that could resist semi-synthetic and synthetic antibiotics. “These include, for example, third- and fourth-generation cephalosporins, which are drugs we try to reserve to fight some of the worst infections,” said Dantas. “It was alarming to find genes from the tribespeople that would deactivate these modern, synthetic drugs.” As for how bacteria could resist drugs that such microbes never before had encountered, the researchers point to the possibility of cross-resistance, when genes that resist natural antibiotics also have the ability to resist related synthetic antibiotics. ”We’ve seen resistance emerge in the clinic to every new class of antibiotics, and this appears to be because resistance mechanisms are a natural feature of most bacteria and are just waiting to be activated or acquired with exposure to antibiotics,” Dantas said.  Science Daily  Original web page at Science Daily


Leading doctors warn that sepsis deaths will not be curbed without radical rethink of research strategy

Leading doctors warn that medical and public recognition of sepsis — thought to contribute to between a third and a half of all hospital deaths — must improve if the number of deaths from this common and potentially life-threatening condition are to fall. In a new Commission, published in The Lancet Infectious Diseases, Professor Jonathan Cohen and colleagues outline the current state of research into this little-understood condition, and highlight priority areas for future investigation.

Sepsis — sometimes misleadingly called “blood poisoning” — is a common condition whereby an infection triggers an extreme immune response, resulting in widespread inflammation, blood clotting, and swelling. Among the early (but not universal) symptoms of sepsis are high temperature and fast breathing; if left untreated, it frequently leads to organ failure and death. Although no specific cure for the condition exists, it can often be treated effectively with intensive medical care including antibiotics and intravenous fluid, if identified early enough. According to Professor Cohen, lead author of the Commission and Emeritus Professor of Infectious Diseases at the Brighton & Sussex Medical School, “Sepsis is both one of the best known yet most poorly understood medical disorders, and one of the most challenging medical conditions in routine clinical practice.”

In the UK, sepsis is thought to kill 37000 people every year — more than three times the number killed by breast cancer or prostate cancer. Although mortality rates from sepsis in the UK and other high-income countries appear to be falling in recent decades, the Commission authors point out that the paucity of accurate estimates of the incidence of sepsis means that the true extent of the condition is poorly understood, and apparently reduced mortality rates may be an artefact of improvements in hospital reporting of milder cases. “The number of people dying from sepsis every year — perhaps as many as six million worldwide — is shocking, yet research into new treatments for the condition seems to have stalled,” says Professor Cohen. “Researchers, clinicians, and policymakers need to radically rethink the way we are researching and diagnosing this devastating condition.”

In low-income and middle-income countries, where most sepsis cases occur outside hospital, there are virtually no data on the condition’s incidence, and the number of people killed by sepsis is likely to far exceed the already high rates in more wealthy countries. Moreover, rising rates of antibiotic resistance globally mean that even if mortality rates from sepsis are improving in some high-income countries, there is no room for complacency. In addition to the high fatality rate from sepsis, survivors are at an increased risk of long-term chronic illness and mental or physical impairment, although research into the long-term consequences of surviving sepsis is relatively scarce, so doctors have little evidence available on which to base long-term care plans for these patients. The Commission outlines a roadmap for future research into sepsis, highlighting a number of critical factors that need to change in the field if treatment and diagnosis of sepsis is to improve. Recommendations include prioritising research into biomarkers for sepsis, which would allow quicker diagnosis; better education of medical staff and improving public awareness to ensure earlier recognition; rethinking clinical trial design; recognising that sepsis affects different patients differently and using the power of modern genetics to develop targeted treatments (“personalised medicine”); and, after dozens of failed trials in recent decades, ensuring that universities and drug companies do not abandon research into new drug treatments.  Science Daily  Original web page at Science Daily


* Survey of salmonella species in Staten Island Zoo’s snakes

To better understand the variety of Salmonella species harbored by captive reptiles, Staten Island Zoo has teamed up with the microbiology department at Wagner College. Eden Stark, a graduate student on the project, her advisor, Christopher Corbo, and the zoo’s curator and head veterinarian Marc Valitutto want to know how many Salmonella species live among the Staten Island Zoo rattlesnakes. The zoo has a long history of exhibiting one of the most comprehensive rattlesnake collections in the world, currently with 21 of 38 species on display. So far, Stark has surveyed 26 species of snakes. “Few other institutions have undertaken such broad scale analysis of Salmonella in snakes,” notes Valitutto. The research will be presented at the American Society for Biochemistry and Molecular Biology (ASBMB) Annual Meeting during Experimental Biology 2015

In particular, the investigators are on the lookout for pathogenic species of Salmonella, such as Salmonella arizonae. This species of Salmonella has been known to cause infections in snakes called osteomyelitis. It has a predilection for the bones, such as the vertebra. The bone may deform, and as the infection spreads, the deformed vertebrae may stop the snake from slithering. The infection may be surgically removed or treated with antibiotics if it’s localized and caught early enough. But if left untreated, the infection may eventually cause the snake to die. “If we do get a snake that is positive for arizonae, we’re concerned,” says Valitutto. “We would not want add something like that to our collection because there’s a possibility it will infect our other reptiles.” Another reason to account for the different Salmonella species is for the safety for the zookeepers. Salmonella “is strictly a pathogen for humans. It’s something that anyone who handles reptiles, even people who keep them at home as pets, has to be very cautious about in handling them or anything that is part of their enclosure,” says Corbo.

To categorize the Salmonella species, Stark isolated the bacteria from snake fecal samples. The feces were collected by seasoned zookeepers at Staten Island Zoo who know how to handle venomous snakes.  As expected, because snakes are natural hosts for Salmonella, Stark found a large number of Salmonella species in the fecal samples. She did find several species of Salmonella that are well-known as human pathogens, such as Salmonella typhimurium which can cause diarrhea, abdominal cramps, vomiting and nausea for about a week. In the few cases where Stark possibly detected the snake pathogen S. arizoniae, the news was interesting to the zoo because the snakes weren’t showing any symptoms evidence of disease. “It’s important for keepers to know that a particular species of snake is carrying a potential pathogen so they can keep an eye on it,” says Corbo.

Corbo adds that the handlers will now know that the tools they use to handle the snakes harboring S. arizonae need to be cleaned with extra care so that they don’t accidentally infect other reptiles, especially snakes. Stark is now delving further into the analysis with the polymerase chain reaction. She is testing each Salmonella species she isolates with the technique to see if the bacteria are expressing proteins known as virulence factors. This detail is important because not every potential pathogen will express virulence factors. The bacteria only become a problem if and when they turn on the expression of virulence factors and become infectious agents (for this reason, Salmonella arizonaie within snakes can even be further subdivided into more pathogenic serotypes). “You can have a species and a subspecies of Salmonella that may not carry the specific genes to cause an infection,” says Corbo. “Just because the species is there, it doesn’t mean it’s a pathogenic form of that species. That’s why it takes a lot of screening to figure out exactly what we are seeing: Is it a true pathogen with the genes necessary to be pathogenic?” Valitutto says the information from the analysis is critical for the zoo’s biosecurity protocol. As he notes, “We don’t want to send animals to other institutions that may be harboring a pathogenic strain of Salmonella.”  Science Daily  Original web page at Science Daily