Tag: Virology

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Common cold viruses originated in camels, just like MERS

There are four globally endemic human coronaviruses which, together with the better known rhinoviruses, are responsible for causing common colds. Usually, infections with these viruses are harmless to humans. DZIF Professor Christian Drosten, Institute of Virology at the University Hospital of Bonn, and his research team have now found the source of “HCoV-229E,” one of the four common cold coronaviruses — it also originates from camels, just like the dreaded MERS virus.

The Middle East respiratory syndrome (MERS) coronavirus was identified in humans for the first time in 2012. It causes severe respiratory tract infections that are often fatal. Dromedaries were confirmed to be its animal source some time ago.

“In our MERS investigations we examined about 1,000 camels for coronaviruses and were surprised to find pathogens that are related to ‘HCoV-229E’, the human common cold virus, in almost six percent of the cases,” says Drosten. Further comparative molecular genetic analysis of common cold viruses in bats, humans and dromedaries suggests that this common cold virus was actually transmitted from camels to humans. Common cold virus evolution could provide a scenario for MERS emergence

Drosten and his team isolated live camel common cold viruses and discovered that these could principally also enter human cells — via the same receptor used by the common cold virus “HCoV-229E.” However, the human immune system is able to defend itself against the camel viruses, just as it can against common cold viruses. Furthermore, tests with human serum and animal common cold viruses showed that there is no immediate risk of an epidemic in humans, because largest part of the human population already has immunity, owing to the widespread immunity against the common cold virus HCoV-229E.

So is this the all-clear for MERS viruses too? “The MERS virus is a strange pathogen: smaller, regionally restricted outbreaks, for example in hospitals, keep occurring. Fortunately, the virus has not adapted well enough to humans, and has consequently been unable to spread globally up to now,” says Drosten. The results of the current investigations on predecessors of the human HCoV-229E virus in camels depict a situation that is similar to the current situation with MERS. These predecessor viruses are also not optimally adapted to humans.

The global spread of HCoV-229E through human-to-human transmission, which is highly likely to have occurred during a past pandemic, gives rise to concern. “Our current study gives us a warning sign regarding the risk of a MERS pandemic — because MERS could perhaps do what HCoV-229E did.” So there is need for action: DZIF researchers are working intensively on researching a vaccine against MERS; it will go into clinical testing early next year.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160818093438.htm  Original web page at Science Daily

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Stress bites! Researchers study mosquito/bird interactions

Research shows stressed-out birds more attractive to mosquitoes, raising fears birds exposed to stressors such as road noise, pesticides and light pollution, will be bitten more often and spread more West Nile virus

When researchers from the University of South Florida (USF) and colleagues investigated how the stress hormone, corticosterone, affects how birds cope with West Nile virus, they found that birds with higher levels of stress hormone were twice as likely to be bitten by mosquitoes that transmit the virus. Their studies have implications for the transmission of other viruses such as Eastern Equine Encephalitis, and perhaps even Zika, both known to be carried by the kind of mosquitoes used in this study. A paper describing their research was published in the Proceedings of the Royal Society B.

“Few studies have considered how stress hormone effects on individuals might influence population dynamics,” said study lead author Dr. Stephanie Gervasi, who conducted the studies while carrying out her postdoctoral work at USF and is now at the Monell Chemical Senses Center in Philadelphia. “For vector-borne diseases such as West Nile virus, the presence of corticosterone could influence pathogen spread through effects on contact rates with the mosquitoes that transmit it. In addition, stress hormones have negative effects on animals including immunosuppression and increased susceptibility to infections, which is why we are now also studying how corticosterone affects the birds’ immune response to the virus.”

According to the researchers, mosquitoes use a variety of cues to locate a target, including carbon dioxide output, body size and temperature. They hypothesized that these signals coming from a bird could convey information about stress hormones making the birds more appealing targets for the insects.

With the effects of corticosterone on mosquito feeding choices unknown, in a series of studies the researchers experimentally manipulated songbird stress hormones levels. Then they examined mosquito feeding preferences, feeding success and productivity as well as the defensive behaviors of birds trying to avoid being bitten.

In several phases of the study, zebra finches were treated with a low or high level of corticosterone and their caged light environment was altered to simulate dusk as the birds were made available to mosquitoes for measured periods of time. Bird and mosquito behavior was observed via video and the mosquitoes were later examined to determine if they had fed on the birds. The researchers also investigated the timing of subsequent mosquito egg-laying after the insects fed on the birds.

“Mosquitoes seem to be able to ‘sniff out’ the stress hormone and key in on individual birds,” said the study’s principal investigator Dr. Lynn Martin, associate professor in the USF Department of Integrative Biology. “The birds injected with higher levels of the hormone were twice as likely to be bitten by mosquitoes, even those hormone-treated birds were much more defensive than untreated ones. Corticosterone treatment increased tail flicks, and head shakes, and other defensive behaviors, but the mosquitoes managed to breach those defenses and feed more on stress hormone-treated birds.”

The study’s broader ecological implications suggest that an elevated stress hormone concentration raises the level of host attractiveness, potentially affecting the transmission of mosquito-borne diseases in a number of ways.

“Stress hormones also altered the relationship between the timing of laying and clutch size in mosquitoes,” said co-principal investigator Dr. Thomas Unnasch, chair and Distinguished USF Health Professor in the Department of Global Health, USF College of Public Health.

Mosquitoes that fed on birds with high stress hormone levels tended to lay different sized clutches of eggs at different rates than mosquitoes fed on control birds. These effects of bird stress on mosquito reproduction suggest that mosquito-feeding choice might also affect disease cycles in nature by changing the number of newborn mosquitoes that could be infected later by stressed birds.

The researchers concluded that the corticosterone levels in their test birds were within the range of normal for birds in the wild when exposed to stressors in natural their environments, such as road noise, pesticides and light pollution.

“Much more work is necessary to further understand on the interplay of host corticosterone, vector-feeding behavior, host defenses and mosquito productivity,” the researchers said.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160810084631.htm Original web page at Science Daily

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* How norovirus gets inside cells: New clues

Norovirus is the most common viral cause of diarrhea worldwide, but scientists still know little about how it infects people and causes disease because the virus grows poorly in the lab. The discovery, in mice, provides new ways to study a virus notoriously hard to work with and may lead to treatments or a vaccine.

Researchers at Washington University School of Medicine in St. Louis have identified the protein that norovirus — shown here in a colored transmission electron micrograph — uses to invade cells. Norovirus is the most common viral cause of diarrhea worldwide, but scientists still know little about how it infects people and causes disease because the virus grows poorly in the lab. The discovery, in mice, provides new ways to study a virus notoriously hard to work with and may lead to treatments or a vaccine.

Now, researchers at Washington University School of Medicine in St. Louis have identified the protein that norovirus uses to invade cells. The discovery, in mice, provides new ways to study a virus notoriously hard to work with and may lead to treatments or a vaccine.

“Our inability to grow the virus in the lab has limited our ability to develop anti-viral agents. If you can’t get the virus to multiply in human cells, how are you going to find compounds that inhibit multiplication?” said Herbert “Skip” Virgin, MD, PhD, the Mallinckrodt Professor and Chair of the Department of Pathology and Immunology and the study’s senior author. “This discovery provides a good basis for our mouse model, which we can then use to understand noroviral pathogenesis and search for treatments in people.” The research is published August 18 in Science.

Norovirus is infamous for causing outbreaks of diarrhea, vomiting and stomach cramps on cruise ships, in military barracks and in other environments where people live in close quarters. For most people, infection leads to an uncomfortable day or two punctuated with frequent trips to the bathroom, but in vulnerable populations such as cancer patients and older people, the disease can be long-lasting and sometimes deadly.

There are many noroviruses, but each is restricted to infecting just one animal species. Human norovirus will not infect any of the species typically used in biomedical research, such as mice, rats or rabbits. Human norovirus won’t grow even in human cells in petri dishes.

“Since human norovirus won’t grow in human cell lines or laboratory animals, you can’t test a drug, you can’t test a vaccine,” Virgin said. “You’d have to do those kinds of studies in people, but it would be better if we can first conduct tests in animal models.”

When mouse norovirus was discovered in 2003, it seemed like a great opportunity to make a mouse model of norovirus infection. The genomes of mouse and human norovirus are very similar, and the viruses even look alike under the electron microscope. Nobody could ever be sure, however, that how mouse norovirus acts in mice is relevant to how human norovirus acts in humans.

Virgin and postdoctoral researchers Craig Wilen, MD, PhD, and Robert Orchard, PhD, thought that if they could identify the reason that mouse norovirus infects only mice and human norovirus infects only humans, they could improve their model of norovirus infection.

The researchers used a genetic tool known as CRISPR-Cas9 to identify mouse genes that are important for mouse noroviral infection. They found that when a gene called CD300lf was knocked down by CRISPR-Cas9, norovirus could not infect the cells. CD300lf codes for a protein on the surface of mouse cells, and the researchers believe the virus latches on to it to get inside the cell.

Furthermore, when the researchers expressed mouse CD300lf protein on the surface of human cells, mouse norovirus was able to infect the human cells and multiply. “Mouse norovirus grew just fine in human cells,” Virgin said. “This tells us that the species restriction is due to the ability to get inside the cells in the first place. Once inside the cells, most likely all the other mechanisms are conserved between human and mouse noroviruses, since the viruses are so similar.”

The researchers also found that mouse norovirus requires a second molecule, or cofactor, to infect cells; CD300lf by itself isn’t enough. But they were unable to nail down the molecule’s identity.

“At this point we know more about what it isn’t than what it is,” said Orchard, a co-lead author on the study. “Every week there’s a new favorite hypothesis. It’s probably a small molecule found in the blood, not a protein.”

It is unusual for a virus to require a cofactor for infection. Their discovery suggests that the lack of a necessary cofactor may be why scientists have had a difficult time growing human norovirus in the lab.

The researchers are working on ways to use human cells with the mouse CD300lf protein to study noroviral infection. One possibility is to use the system to screen drugs to block viral multiplication. Such drugs could be administered prophylactically to people around the epicenter of an outbreak, or as a treatment for immunocompromised individuals.

The discovery of the mouse receptor for norovirus also could lead to a better understanding of how the virus causes disease.

“We still don’t even know if the virus infects epithelial cells or immune cells, and that matters if you want to develop a vaccine,” said Wilen, a co-lead author on the study. “We have developed a knockout mouse that lacks CD300lf, and we are using it to identify the cell types involved. We’re hoping that a better understanding of the pathogenesis will lead to better ways to treat or prevent this very common disease.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/08/160818150000.htm Original web page at Science Daily

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Zika infection may affect adult brain cells

Concerns over the Zika virus have focused on pregnant women due to mounting evidence that it causes brain abnormalities in developing fetuses. However, new research in mice from scientists at The Rockefeller University and La Jolla Institute for Allergy and Immunology suggests that certain adult brain cells may be vulnerable to infection as well. Among these are populations of cells that serve to replace lost or damaged neurons throughout adulthood, and are also thought to be critical to learning and memory.

“This is the first study looking at the effect of Zika infection on the adult brain,” says Joseph Gleeson, adjunct professor at Rockefeller, head of the Laboratory of Pediatric Brain Disease, and Howard Hughes Medical Institute investigator. “Based on our findings, getting infected with Zika as an adult may not be as innocuous as people think.”

Although more research is needed to determine if this damage has long-term biological implications or the potential to affect behavior, the findings suggest the possibility that the Zika virus, which has become widespread in Central and South America over the past eight months, may be more harmful than previously believed. The new findings were published in Cell Stem Cell on August 18.

“Zika can clearly enter the brain of adults and can wreak havoc,” says Sujan Shresta, a professor at the La Jolla Institute of Allergy and Immunology. “But it’s a complex disease — it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle, and now we know what to look for.”

Early in gestation, before our brains have developed into a complex organ with specialized zones, they are comprised entirely of neural progenitor cells. With the capability to replenish the brain’s neurons throughout its lifetime, these are the stem cells of the brain. In healthy individuals, neural progenitor cells eventually become fully formed neurons, and it is thought that at some point along this progression they become resistant to Zika, explaining why adults appear less susceptible to the disease.

But current evidence suggests that Zika targets neural progenitor cells, leading to loss of these cells and to reduced brain volume. This closely mirrors what is seen in microcephaly, a developmental condition linked to Zika infection in developing fetuses that results in a smaller-than-normal head and a wide variety of developmental disabilities.

The mature brain retains niches of these neural progenitor cells that appear to be especially impacted by Zika. These niches — in mice they exist primarily in two regions, the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus — are vital for learning and memory.

Gleeson and his colleagues suspected that if Zika can infect fetal neural progenitor cells, it wouldn’t be a far stretch for them to also be able to infect these cells in adults. In a mouse model engineered by Shresta and her team to mimic Zika infection in humans, fluorescent biomarkers illuminated to reveal that adult neural progenitor cells could indeed be hijacked by the virus.

“Our results are pretty dramatic — in the parts of the brain that lit up, it was like a Christmas tree,” says Gleeson. “It was very clear that the virus wasn’t affecting the whole brain evenly, like people are seeing in the fetus. In the adult, it’s only these two populations that are very specific to the stem cells that are affected by virus. These cells are special, and somehow very susceptible to the infection.”

The researchers found that infection correlated with evidence of cell death and reduced generation of new neurons in these regions. Integration of new neurons into learning and memory circuits is crucial for neuroplasticity, which allows the brain to change over time. Deficits in this process are associated with cognitive decline and neuropathological conditions, such as depression and Alzheimer’s disease.

Gleeson and colleagues recognize that healthy humans may be able to mount an effective immune response and prevent the virus from attacking. However, they suggest that some people, such as those weakened immune systems, may be vulnerable to the virus is a way that has not yet been recognized.

“In more subtle cases, the virus could theoretically impact long-term memory or risk of depression,” says Gleeson, “but tools do not exist to test the long-term effects of Zika on adult stem cell populations.”

In addition to microcephaly, Zika has been linked to Guillain-Barré syndrome, a rare condition in which the immune system attacks parts of the nervous system, leading to muscle weakness or even paralysis. “The connection has been hard to trace since Guillain-Barré usually develops after the infection has cleared,” says Shresta. “We propose that infection of adult neural progenitor cells could be the mechanism behind this.”

There are still many unanswered questions, including exactly how translatable findings in this mouse model are to humans. Gleeson’s findings in particular raise questions such as: Does the damage inflicted on progenitor cells by the virus have lasting biological consequences, and can this in turn affect learning and memory? Or, do these cells have the capability to recover? Nonetheless, these findings raise the possibility that Zika is not simply a transient infection in adult humans, and that exposure in the adult brain could have long-term effects.

“The virus seems to be traveling quite a bit as people move around the world,” says Gleeson. “Given this study, I think the public health enterprise should consider monitoring for Zika infections in all groups, not just pregnant women.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/08/160818131134.htm Original web page at Science Daily

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* Gene therapy treats all muscles in the body in muscular dystrophy dogs

Muscular dystrophy, which affects approximately 250,000 people in the U.S., occurs when damaged muscle tissue is replaced with fibrous, fatty or bony tissue and loses function. For years, scientists have searched for a way to successfully treat the most common form of the disease, Duchenne Muscular Dystrophy (DMD), which primarily affects boys. Now, a team of University of Missouri researchers have successfully treated dogs with DMD and say that human clinical trials are being planned in the next few years.

“This is the most common muscle disease in boys, and there is currently no effective therapy,” said Dongsheng Duan, the study leader and the Margaret Proctor Mulligan Professor in Medical Research at the MU School of Medicine. “This discovery took our research team more than 10 years, but we believe we are on the cusp of having a treatment for the disease.”

Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of a protein known as “dystrophin.” Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. Affected boys lose their ability to walk and breathe as they get older. This places significant limitations on individuals afflicted with the disease. Dystrophin also is one of the largest genes in the human body.

“Due to its size, it is impossible to deliver the entire gene with a gene therapy vector, which is the vehicle that carries the therapeutic gene to the correct site in the body,” Duan said. “Through previous research, we were able to develop a miniature version of this gene called a microgene. This minimized dystrophin protected all muscles in the body of diseased mice.”

However, it took the team more than 10 years to develop a strategy that can safely send the micro-dystrophin to every muscle in a dog that is afflicted by the disease. The dog has a body size similar to that of an affected boy. Success in the dog will set the foundation for human tests.

In this latest study, the MU team demonstrated for the first time that a common virus can deliver the microgene to all muscles in the body of a diseased dog. The dogs were injected with the virus when they were two to three months old and just starting to show signs of DMD. The dogs are now six to seven months old and continue to develop normally

“The virus we are using is one of the most common viruses; it is also a virus that produces no symptoms in the human body, making this a safe way to spread the dystrophin gene throughout the body,” Duan said. “These dogs develop DMD naturally in a similar manner as humans. It’s important to treat DMD early before the disease does a lot of damage as this therapy has the greatest impact at the early stages in life.”

https://www.sciencedaily.com/  Science  Daily

https://www.sciencedaily.com/releases/2015/10/151022141722.htm  Original web page at Science Daily

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Scientists identify immunological profiles of people who make powerful HIV antibodies

People living with HIV who naturally produce broadly neutralizing antibodies (bNAbs) that may help suppress the virus have different immunological profiles than people who do not, researchers report. While bNAbs cannot completely clear HIV infections in people who have already acquired the virus, many scientists believe a successful preventive HIV vaccine must induce bNAbs. The new findings indicate that bNAb production may be associated with specific variations in individual immune functions that may be triggered by unchecked HIV infection. Defining how to safely replicate these attributes in HIV-uninfected vaccine recipients may lead to better designed experimental vaccines to protect against HIV. The study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Researchers led by a team at Duke University identified these immunologic variations by studying blood samples collected from people living with HIV by the NIAID-supported Center for HIV/AIDS Vaccine Immunology (CHAVI). The team compared blood samples from the 51 individuals with the highest level of bNAbs with samples taken from 51 individuals with few or no bNAbs present. The analysis performed revealed that many variations in immune cell function triggered by chronic HIV infection are associated with high levels of bNAbs. The specific changes included a higher frequency of antibodies that attack one’s own cells, called autoantibodies; fewer immune regulatory T cells, which were also less active in these individuals; and a higher frequency of memory T follicular helper immune cells.

With this immune system configuration, the activity of antibody-producing immune cells called B cells may be less restricted because they are supported by T follicular helper cells and may be hindered by regulatory T cells. This, in turn, could lead to more efficient production of protective bNAbs against HIV. These findings support approaches to developing an HIV vaccine that involve modifying an individual’s immune system to mimic these conditions through the addition of vaccine boosters called adjuvants or other means.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160729143030.htm Original web page at Science Daily

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DNA’s dynamic nature makes it well-suited to serve as the blueprint of life

A new study could explain why DNA and not RNA, its older chemical cousin, is the main repository of genetic information. The DNA double helix is a more forgiving molecule that can contort itself into different shapes to absorb chemical damage to the basic building blocks — A, G, C and T — of genetic code. In contrast, when RNA is in the form of a double helix it is so rigid and unyielding that rather than accommodating damaged bases, it falls apart completely.

The research, published August 1, 2016 in the journal Nature Structural and Molecular Biology, underscores the dynamic nature of the DNA double helix, which is central to maintaining the stability of the genome and warding off ailments like cancer and aging. The finding will likely rewrite textbook coverage of the difference between the two purveyors of genetic information, DNA and RNA.

“There is an amazing complexity built into these simple beautiful structures, whole new layers or dimensions that we have been blinded to because we didn’t have the tools to see them, until now,” said Hashim M. Al-Hashimi, Ph.D., senior author of the study and professor of biochemistry at Duke University School of Medicine.

DNA’s famous double helix is often depicted as a spiral staircase, with two long strands twisted around each other and steps composed of four chemical building blocks called bases. Each of these bases contain rings of carbon, along with various configurations of nitrogen, oxygen, and hydrogen. The arrangement of these atoms allow G to pair with C and A to pair with T, like interlocking gears in an elegant machine.

When Watson and Crick published their model of the DNA double helix in 1953, they predicted exactly how these pairs would fit together. Yet other researchers struggled to provide evidence of these so-called Watson-Crick base pairs. Then in 1959, a biochemist named Karst Hoogsteen took a picture of an A-T base pair that had a slightly skewed geometry, with one base rotated 180 degrees relative to the other. Since then, both Watson-Crick and Hoogsteen base pairs have been observed in still images of DNA.

Five years ago, Al-Hashimi and his team showed that base pairs constantly morph back and forth between Watson-Crick and the Hoogsteen configurations in the DNA double helix. Al-Hashimi says that Hoogsteen base pairs typically show up when DNA is bound up by a protein or damaged by chemical insults. The DNA goes back to its more straightforward pairing when it is released from the protein or has repaired the damage to its bases.

“DNA seems to use these Hoogsteen base pairs to add another dimension to its structure, morphing into different shapes to achieve added functionality inside the cell,” said Al-Hashimi.

Al-Hashimi and his team wanted to know if the same phenomenon might also be occurring when RNA, the middleman between DNA and proteins, formed a double helix. Because these shifts in base pairing involve the movement of molecules at an atomic level, they are difficult to detect by conventional methods. Therefore, Al-Hashimi’s graduate student Huiqing Zhou used a sophisticated imaging technique known as NMR relaxation dispersion to visualize these tiny changes. First, she designed two model double helices — one made of DNA and one made of RNA. Then, she used the NMR technique to track the flipping of individual G and A bases that make up the spiraling steps, pairing up according to Watson-Crick or Hoogsteen rules.

Prior studies indicated that at any given time, one percent of the bases in the DNA double helix were morphing into Hoogsteen base pairs. But when Zhou looked at the corresponding RNA double helix, she found absolutely no detectable movement; the base pairs were all frozen in place, stuck in the Watson-Crick configuration.

The researchers wondered if their model of RNA was an unusual exception or anomaly, so they designed a wide range of RNA molecules and tested them under a wide variety of conditions, but still none appeared to contort into the Hoogsteen configuration. They were concerned that the RNA might actually be forming Hoogsteen base pairs, but that they were happening so quickly that they weren’t able to catch them in the act. Zhou added a chemical known as a methyl group to a specific spot on the bases to block Watson-Crick base pairing, so the RNA would be trapped in the Hoogsteen configuration. She was surprised to find that rather than connecting through Hoogsteen base pairs, the two strands of RNA came apart near the damage site.

“In DNA this modification is a form of damage, and it can readily be absorbed by flipping the base and forming a Hoogsteen base pair. In contrast, the same modification severely disrupts the double helical structure of RNA,” said Zhou, who is lead author of the study.

The team believes that RNA doesn’t form Hoogsteen base pairs because its double helical structure (known as A-form) is more compressed than DNA’s (B-form) structure. As a result, RNA can’t flip one base without hitting another, or without moving around atoms, which would tear apart the helix.

“For something as fundamental as the double helix, it is amazing that we are discovering these basic properties so late in the game,” said Al-Hashimi. “We need to continue to zoom in to obtain a deeper understanding regarding these basic molecules of life.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160801113823.htm Original web page at Science Daily

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Viruses revealed to be a major driver of human evolution

The constant battle between pathogens and their hosts has long been recognized as a key driver of evolution, but until now scientists have not had the tools to look at these patterns globally across species and genomes. In a new study, researchers apply big-data analysis to reveal the full extent of viruses’ impact on the evolution of humans and other mammals.

Their findings suggest an astonishing 30 percent of all protein adaptations since humans’ divergence with chimpanzees have been driven by viruses.

“When you have a pandemic or an epidemic at some point in evolution, the population that is targeted by the virus either adapts, or goes extinct. We knew that, but what really surprised us is the strength and clarity of the pattern we found,” said David Enard, Ph.D., a postdoctoral fellow at Stanford University and the study’s first author. “This is the first time that viruses have been shown to have such a strong impact on adaptation.”

The study was recently published in the journal eLife and will be presented at The Allied Genetics Conference, a meeting hosted by the Genetics Society of America, on July 14.

Proteins perform a vast array of functions that keep our cells ticking. By revealing how small tweaks in protein shape and composition have helped humans and other mammals respond to viruses, the study could help researchers find new therapeutic leads against today’s viral threats.

“We’re learning which parts of the cell have been used to fight viruses in the past, presumably without detrimental effects on the organism,” said the study’s senior author, Dmitri Petrov, Ph.D., Michelle and Kevin Douglas Professor of Biology and Associate Chair of the Biology Department at Stanford. “That should give us an insight on the pressure points and help us find proteins to investigate for new therapies.”

Previous research on the interactions between viruses and proteins has focused almost exclusively on individual proteins that are directly involved in the immune response — the most logical place you would expect to find adaptations driven by viruses. This is the first study to take a global look at all types of proteins.

“The big advancement here is that it’s not only very specialized immune proteins that adapt against viruses,” said Enard. “Pretty much any type of protein that comes into contact with viruses can participate in the adaptation against viruses. It turns out that there is at least as much adaptation outside of the immune response as within it.”

The team’s first step was to identify all the proteins that are known to physically interact with viruses. After painstakingly reviewing tens of thousands of scientific abstracts, Enard culled the list to about 1,300 proteins of interest. His next step was to build big-data algorithms to scour genomic databases and compare the evolution of virus-interacting proteins to that of other proteins.

The results revealed that adaptations have occurred three times as frequently in virus-interacting proteins compared with other proteins.

“We’re all interested in how it is that we and other organisms have evolved, and in the pressures that made us what we are,” said Petrov. “The discovery that this constant battle with viruses has shaped us in every aspect — not just the few proteins that fight infections, but everything — is profound. All organisms have been living with viruses for billions of years; this work shows that those interactions have affected every part of the cell.”

Viruses hijack nearly every function of a host organism’s cells in order to replicate and spread, so it makes sense that they would drive the evolution of the cellular machinery to a greater extent than other evolutionary pressures such as predation or environmental conditions. The study sheds light on some longstanding biological mysteries, such as why closely-related species have evolved different machinery to perform identical cellular functions, like DNA replication or the production of membranes. Researchers previously did not know what evolutionary force could have caused such changes. “This paper is the first with data that is large enough and clean enough to explain a lot of these puzzles in one fell swoop,” said Petrov.

The team is now using the findings to dig deeper into past viral epidemics, hoping for insights to help fight disease today. For example, HIV-like viruses have swept through the populations of our ancestors as well as other animal species at multiple points throughout evolutionary history. Looking at the effects of such viruses on specific populations could yield a new understanding of our constant war with viruses — and how we might win the next big battle.

were divided into 12 experimental groups and one control group, also impressive, because most studies have two or three experimental groups.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160630102038.htm  Original web page at Science Daily

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HPV vaccine can protect women across a broad age range

A research paper published in The Lancet Infectious Diseases reported that the human papillomavirus (HPV) vaccine is safe and efficacious across a wide age range of women. The international study found that it protects against HPV infection in women older than 26 years. Vaccination programs worldwide currently target routine vaccination of women 26 years and younger.

The study recruited women in 12 countries across four continents. Cosette Wheeler, PhD, at The University of New Mexico Comprehensive Cancer Center, was the lead author of the report.

The human papillomaviruses cause cancer of the cervix, anus, and middle throat. Five types of HPV account for about 85 percent of all invasive cervical cancer cases. HPV vaccines are expected to prevent most of these cancer cases.

Many countries routinely vaccinate girls and boys 25 years and younger, although vaccination rates in the United States remain low. In the US, only about 40 percent of girls and 21 percent of boys receive the three-dose vaccination series. The earlier the vaccine is given, the more efficacious it can be.

This study focused on the benefit of vaccinating women 26 years and older. Infection with HPV can take place at any time throughout adulthood and women in this age group may have already been exposed to HPV. The study showed that women in this age group were still protected from HPV infections.

The scientists followed each woman for four to seven years. They found that the vaccine protected the women against HPV infections during the follow-up period and that the women were protected from many types of HPV across a broad age range. These study results are essential to new approaches in cancer prevention, particularly those that are investigating combined approaches of cervical screening and vaccination in adult women.

Cosette Wheeler, PhD is a UNM Regents Professor in the Departments of Pathology and Obstetrics and Gynecology at the University of New Mexico Health Sciences Center. She holds the Victor and Ruby Hansen Surface Endowed Chair in Translational Medicine and Public Health. Her New Mexico research group has contributed for over 20 years to understanding the molecular epidemiology of human papillomaviruses (HPV) in cervical precancer and cancer among Native American, Hispanic and non-Hispanic women of the southwest and on a global basis. She has overseen a number of large-scale multidisciplinary population-based projects that have ultimately enabled advances in primary (HPV vaccines) and secondary cervical cancer prevention (Pap and HPV tests).

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160713115215.htm  Original web page at Science Daily

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* Model helps identify drugs to treat cat eye infections

It’s a problem veterinarians see all the time, but there are few treatments. Feline herpes virus 1 (FHV-1) is a frequent cause of eye infections in cats, but the drugs available to treat these infections must be applied multiple times a day and there is scant scientific evidence to support their use.

Now scientists at the Baker Institute for Animal Health at Cornell’s College of Veterinary Medicine have developed a model system that can be used to test drugs for treating these eye infections, and early results have pointed to a new drug for treating FHV-1 that will soon head to clinical trials. The work is reported in the Journal of General Virology.

“Herpes-induced cornea infections are a big problem in cats,” says Dr. Gerlinde Van de Walle, who led the study. Cats infected with FHV-1 will blink continuously, squint and have a teary, sore-looking eye or eyes. “If not treated, FHV-1 infection can eventually lead to blindness,” she says.

“We wanted to develop a model system that could predict whether an antiviral drug would work against FHV-1 in cats,” says Van de Walle. They were also searching for an easy way to identify drugs that could be given only once every 24 hours, because, as vets and many cat owners know, giving medication to a cat multiple times a day can be a difficult, painful thing to accomplish. Smearing ointment in a cat’s eyes might be easy the first and second time, but once the cat learns what you’re up to with that little tube, she will most likely hide or fight.

Van de Walle and her team used tissues donated from cats that died of causes other than eye disease. The outer clear layer of the eye, called the cornea, is shaped like a contact lens but has the consistency of Jell-O. To maintain the natural, dome-shaped structure of these corneas under laboratory conditions, the team gently filled them with agarose, waited for the agarose to firm up, then turned them over and kept them in a liquid medium. The model better resembles what happens in the eyes of a cat compared with using a single layer of cells in a dish and can, therefore, better predict what to expect in the animal.

To use these petri plate corneas as a model of FHV-1 infection, they applied the virus to some of the corneas and left others uninfected. They then tested the effectiveness of two drugs that are used for topical treatment of FHV-1 eye infections in cats: cidofovir, which is frequently used in the clinic, and acyclovir, which has shown some activity when given frequently. Both drugs cleared the infection when applied every 12 hours, but cidofovir was more effective.

Taking it a step further, Van de Walle and her team used the model system to identify another drug for treating FHV-1 infections. The antiretroviral drug raltegravir is commonly used in humans to treat HIV infections, and although some reports indicated it could be effective against herpes viruses, it had never been used to treat FHV-1 in cats before.

“We found that it is very effective against FHV-1. It even worked when we applied the drug only once every 24 hours,” says Van de Walle. This means raltegravir could be just as efficient as the other drugs available for treating FHV-1 infections, but would only have to be administered once daily. Van de Walle says she hopes eventually to see the drug tested in a well-controlled clinical trial.

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https://www.sciencedaily.com/releases/2016/07/160719123900.htm Original web page at Science Daily

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HPV vaccine reduced cervical abnormalities in young women

Young women who received the human papillomavirus (HPV) vaccine through a school-based program had fewer cervical cell anomalies when screened for cervical cancer, found a new study in CMAJ (Canadian Medical Association Journal).

“Eight years after a school-based HPV vaccination program was initiated in Alberta, 3-dose HPV vaccination has demonstrated early benefits, particularly against high-grade cervical abnormalities, which are more likely to progress to cervical cancer,” writes Dr. Huiming Yang, Medical Officer of Health and Medical Director, Screening Programs, Alberta Health Services, Calgary, Alberta, with coauthors.

Alberta has both a school-based HPV vaccination program and a population-based screening program for cervical cancer. In 2008, the province introduced HPV vaccination for Grade 5 girls (aged 10-11) and a 3-year catch-up program for Grade 9 girls (aged 14-15); in 2014, it was expanded to include boys. The program provides 3 doses of the vaccine that protects against two strains of HPV, which account for 70% of all cases of cervical cancer.

To determine whether HPV vaccination had an impact on Papanicolaou (Pap) test results, Alberta researchers looked at data on the first cohort of women who participated in both the school vaccination program and cervical cancer screening. The 10 204 women in the study population were born between 1994 and 1997 (aged 18 to 21 years) and lived in the province before 2008.

Of the total, 1481 (14.5%) were cases — that is, they had cervical anomalies detected during screening — and the remaining 8723 (85.5%) were controls — with no cervical abnormalities detected. Among cases, most (1384, 93.5%) had low-grade cervical abnormalities, and the remaining 97 (6.5%) had high-grade abnormalities.

More than half of the study participants (56%) were unvaccinated, and 44% had received 1 or more doses of the HPV vaccine before being screened for cervical cancer. Of the women who had been vaccinated, 84% received 3 or more doses. Among the unvaccinated women, 16.1% had cervical abnormalities, compared with 11.8% in the fully vaccinated group.

The authors note that effective HPV vaccination with broad uptake will affect the harms and benefits of cervical screening.

“With population-based HPV vaccination, guidelines for cervical cancer screening may need to include a later age for screening initiation age and/or a longer interval between screenings,” they write.

The authors hope that their findings and future research will lead to improved primary and secondary prevention efforts, with integration of HPV vaccination and cervical cancer screening programs.

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https://www.sciencedaily.com/releases/2016/07/160704145722.htm  Original web page at Science Daily

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On the path to controlled gene therapy

The ability to switch disease-causing genes on and off remains a dream for many physicians, research scientists and patients. Research teams from across the world are busy turning this dream into a reality, including a team of researchers from Charité — Universitätsmedizin Berlin and the Max Planck Institute for Medical Research in Heidelberg. Led by Dr. Mazahir T. Hasan, and working under the auspices of the NeuroCure Cluster of Excellence, the team has successfully programmed a virus to transport the necessary genetic material to affected tissue and nerve cells inside the body.

A report on their new virus-based method, which delivers instructions to the host genome without becoming part of it, has been published in the journal Molecular Therapy Nucleic Acids.

From cancer to Alzheimer’s disease, many life-threatening diseases can only be treated using drug-based treatment options, if at all. Many of these treatments are non-specific in nature, or even ineffective. In some cases, the undesirable side-effects may even outweigh the desirable ones. This is because indiscriminate treatments damage healthy cells, impairing their ability to communicate with other cells; as a result, it is hoped that genetically produced and modified mediators will be able to selectively target diseased cells, and improve the way treatment is delivered. “In the laboratory, we use attenuated, i.e. non-replicating viruses that are known as recombinant adeno-associated viruses (rAAV). We use them to transport genetically encoded material into live organisms affected by disease,” explains Dr. Hasan. “This approach opens up a whole range of options which, in the future, may allow us to treat and heal various diseases.”

By successfully completing the initial step of testing this new method using an animal model, the researchers have laid the groundwork for future genetic treatments for use in humans. Before these can be used, however, they will need to be tested to ensure their safety. It is already known that rAAVs can transport genetically encoded material into any type of cell and tissue, including the brain, and that, once inside the cells, they are capable of repeatedly switching gene therapy applications on and off again. This on/off switch is controlled chemically, via either food intake or drinking water: “The fact that gene function can be switched on and off in this manner is of particular value, and renders the method a perfect candidate for use in controlled gene therapy,” emphasizes Dr. Hasan

The fact that rAAV-infected cells do not trigger any form of measurable immune response and that their genetic material remains completely intact represents an additional benefit. While this does not mean that future gene therapy applications are guaranteed to be successful, the researchers are full of confidence for the future. “We are still at the laboratory stage,” says Dr. Hasan, adding: “Once additional safety options are in place, this development could spearhead innovation, heralding in a time when the transfer of genetically encoded material will be used to heal severe diseases, including neurological ones such as Parkinson’s disease, Alzheimer’s disease and epilepsy.”

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https://www.sciencedaily.com/releases/2016/07/160719110225.htm  Original web page at Science Daily

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Itchy inflammation of mosquito bites helps viruses replicate

Mosquito bite sites are not just itchy, irritating nuisances — they also make viral infections spread by the insects far worse, new research has found.

The study, led by the University of Leeds, found that inflammation where the insect has bitten not only helps a virus such as Zika or dengue establish an infection in the body more quickly, but that it also helps it to spread around the body, increasing the likelihood of severe illness.

“Mosquito bites are not just annoying — they are key for how these viruses spread around your body and cause disease,” said Dr Clive McKimmie, a research fellow at the School of Medicine and senior author of the study.

“We now want to look at whether medications such as anti-inflammatory creams can stop the virus establishing an infection if used quickly enough after the bite inflammation appears.”

In the new research, published in the journal Immunity, the investigators used mouse models to study the bites of the Aedes aegypti mosquito, the species that spreads infections such as Zika, dengue and Chikungunya.

When a mosquito bites, it injects saliva into the skin. The saliva triggers an immune response in which white blood cells called neutrophils and myeloid cells rush to the site.

But instead of helping, some of these cells get infected and inadvertently replicate the virus, the researchers found.

The team injected viruses into the skin of the mice with or without the presence of a mosquito bite at the injection site and compared the reaction.

In the absence of mosquito bites and their accompanying inflammation, the viruses failed to replicate well, whereas the presence of a bite resulted in a high virus level in the skin.

“This was a big surprise we didn’t expect,” said Dr McKimmie, whose team worked alongside colleagues at the University of Glasgow. “These viruses are not known for infecting immune cells.

“And sure enough, when we stopped these immune cells coming in, the bite did not enhance the infection anymore.”

Despite the enormous disease burden of mosquito-borne viral infections — they are responsible for hundreds of millions of cases across the world — there are few specific therapies or vaccines.

“This research could be the first step in repurposing commonly available anti-inflammatory drugs to treat bite inflammation before any symptoms set in,” said Dr McKimmie, whose study was funded by the Medical Research Council.

“We think creams might act as an effective way to stop these viruses before they can cause disease.” He added that if it is proven to be effective, this approach could work against a multitude of other viruses. “Nobody expected Zika, and before that nobody expected Chikungunya,” he said.

“There are estimated to be hundreds of other mosquito-borne viruses out there and it’s hard to predict what’s going to start the next outbreak.”

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https://www.sciencedaily.com/releases/2016/06/160621132526.htm  Original web page at Science Daily

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A new way to nip AIDS in the bud

Now, University of Utah researchers found a way to turn protease into a double-edged sword: They showed that if they delay the budding of new HIV particles, protease itself will destroy the virus instead of helping it spread. They say that might lead, in about a decade, to new kinds of AIDS drugs with fewer side effects.

“We could use the power of the protease itself to destroy the virus,” says virologist Saveez Saffarian, an associate professor of physics and astronomy at the University of Utah and senior author of the study released today by PLOS Pathogens, an online journal published by the Public Library of Science.

So-called cocktails or mixtures of protease inhibitors emerged in the 1990s and turned acquired immune deficiency syndrome into a chronic, manageable disease for people who can afford the medicines. But side effects include fat redistribution in the body, diarrhea, nausea, rash, stomach pain, liver toxicity, headache, diabetes and fever.

“They have secondary effects that hurt patients,” says Mourad Bendjennat, a research assistant professor of physics and astronomy and the study’s first author. “And the virus becomes resistant to the inhibitors. That’s why they use cocktails.”

Bendjennat adds that by discovering the molecular mechanism in which protease interacts with HIV, “we are developing a new approach that we believe may be very efficient in treating the spread of HIV.”

However, he and Saffarian emphasize the research is basic, and that it will be a decade before more research might develop the approach into news AIDS treatments.

Inside a cell infected by HIV, new virus particles are constructed largely with a protein named Gag. Protease enzymes are incorporated into new viral particles as they are built, and are thought to be activated after the new particles “bud” out of infected cell and then break off from it.

The particles start to bud from the host cell in a saclike container called a vesicle, the neck of which eventually separates from the outer membrane of the infected cell. “Once the particles are released, the proteases are activated and the particles transform into mature HIV, which is infectious,” Saffarian says.

“There is an internal mechanism that dictates activation of the protease, which is not well understood,” he adds. “We found that if we slow the budding process, the protease activates while the HIV particle is still connected to the outer membrane of host infected cell. As a result, it chews out all the proteins inside the budding HIV particle, and those essential enzymes and proteins leak back into the host cell. The particle continues to bud out and release from the cell, but it is not infectious anymore because it doesn’t have the enzymes it needs to mature.”

The scientists found they could slow HIV particles from budding out of cells by interfering with how they interact with proteins named ESCRTs (pronounced “escorts”), or “endosomal sorting complexes required for transport.”

ESCRTs are involved in helping pinch off budding HIV particles — essentially cutting them from the infected host cell.

Saffarian says scientific dogma long has held “that messing up the interactions of the virus with ESCRTs results in budding HIV particles permanently getting stuck on the host cell membrane instead of releasing.” Bendjennat says several studies in recent years indicated that the particles do get released, casting some doubt on the long held dogma.

The new study’s significance “is about the molecular mechanism: When the ESCRT machinery is altered, there is production of viruslike particles that are noninfectious,” he says. “This study explains the molecular mechanism of that.”

“We found HIV still releases even when early ESCRT interactions are intentionally compromised, however, with a delay,” Saffarian says. “They are stuck for a while and then they release. And by being stuck for a while, they lose their internal enzymes due to early protease activation and lose their infectivity.”

Bendjennat says by delaying virus budding and speeding “when the protease gets activated, we are now capable of using it to make new released viruses noninfectious”

The experiments used human skin cells grown in tissue culture. It already was known that new HIV particles assemble the same way whether the infected host cell is a skin cell, certain other cells or the T-cell white blood cell infected by the virus to cause AIDS. The experiments involved both live HIV and so-called viruslike particles.

Bendjennat and Saffarian genetically engineered mutant Gag proteins. A single HIV particle is made of some 2,000 Gag proteins and 120 copies of proteins known as Gag-Pol, as well as genetic information in the form of RNA. Pol includes protease, reverse transcriptase and integrase — the proteins HIV uses to replicate.

The mutant Gag proteins were designed to interact abnormally with two different ESCRT proteins, named ALIX and Tsg101.

When the researchers interfered with ALIX, release was delayed 75 minutes, reducing by half the infectivity of the new virus particle. When the scientists interfered with Tsg101, release was delayed 10 hours and new HIV particles were not infectious.

The scientists also showed that how fast an HIV particle releases from an infected cell depends on how much enzyme cargo it carries in the form of Pol proteins. By interfering with ESCRT proteins during virus-release experiments with viruslike particles made only of Gag protein but none of the normal Pol enzymes, the 75-minute delay shrank to only 20 minutes, and the 10-hour delay shrank to only 50 minutes.

“When the cargo is large, the virus particle needs more help from the ESCRTs to release on a timely fashion,” Saffarian says.

Because HIV carries a large cargo, it depends on ESCRTs to release from an infected cell, so ESCRTs are good targets for drugs to delay release and let HIV proteases leak back into the host cell, making new HIV particles noninfectious, he says.

Bendjennat says other researchers already are looking for drugs to block ESCRT proteins in a way that would prevent the “neck” of the budding HIV particle from pinching off or closing, thus keeping it connected to the infected cell. But he says the same ESCRTs are needed for cell survival, so such drugs would be toxic.

Instead, the new study suggests the right approach is to use low-potency ESCRT-inhibiting drugs that delay HIV release instead of blocking it, rendering it noninfectious with fewer toxic side effects, he adds.

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Neurologic symptoms common in early HIV infection

A team led by researchers from UCSF and Yale has found that half of people newly infected with HIV experience neurologic issues. These neurologic findings are generally not severe and usually resolve after participants started anti-retroviral therapy.

“We were surprised that neurologic findings were so pervasive in participants diagnosed with very recent HIV infection,” said study lead author, Joanna Hellmuth, MD, MHS, clinical fellow in UCSF’s Department of Neurology. “While the findings were mild, it is clear that HIV affects the nervous system within days of infection. Since the majority of these neurologic issues were resolved with treatment, our study reinforces recommendations that people at risk for HIV test often and start antiretroviral treatment immediately if they are infected.”

The research will be published in the June 10, 2016, issue of Neurology, the medical journal of the American Academy of Neurology.

The team examined 139 participants in the RV254 Thai cohort who were recently infected with HIV. The time from infection to entry into the study ranged from 3 to 56 days with a median of 19 days. At this stage, participants would not test positive on the common antibody tests for HIV since they have not been infected long enough for a robust specific immune response to take place. Fifty-three percent had neurologic findings, with a third experiencing cognitive deficits, a quarter having motor issues, and nearly 20 percent experiencing neuropathy. Many experienced more than one symptom. One participant was diagnosed with Guillain-Barré Syndrome, the only severe case found in the cohort.

“In the early days of the epidemic in San Francisco, approximately 10 percent of patients with recent HIV infection presented with dramatic neurological disease. But that was likely due to patients coming in early because of the severity of symptoms they were experiencing. The Thai cohort has given us an opportunity to look at a broad range of newly infected patients, analyze their neurological functioning systematically and follow them over time. We are gaining deeper insights into the degree to which early HIV affects the nervous system,” said study senior author, Serena Spudich, MD, Yale associate professor of neurology.

All participants were offered and commenced antiretroviral treatment at diagnosis. Ninety percent of the issues present at diagnosis were resolved after one month of treatment, but 9 percent of the participants had neurologic symptoms that were still not resolved six months after starting therapy. In addition, neurological symptoms were associated with higher levels of HIV found in participants’ blood.

The study participants underwent extensive neurologic assessments. Self reported symptoms were correlated with objective neuropsychological testing. In addition, a quarter of participants opted to undergo a lumbar puncture and almost half of the patients agreed to undergo a MRI.

“This is one of the first comprehensive studies scrutinizing the involvement of the nervous system in early infection. Since we have been able to maintain the cohort for five years now, we will be able to study whether there are any persistent abnormalities that need to be addressed. Additionally, the ubiquity of symptoms in early infection found in this study reinforces the need for the brain to be considered as a compartment containing latent HIV as we design cure studies,” said study co-author, Victor Valcour, MD, PhD, UCSF professor of neurology.

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https://www.sciencedaily.com/releases/2016/06/160613105753.htm Original web page at Science Daily

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Making virus sensors cheap and simple: New method detects single viruses in urine

Scientists at The University of Texas at Austin have developed a new method to rapidly detect a single virus in urine, as reported this week in the journal Proceedings of the National Academy of Sciences.

While the technique presently works on just one virus, scientists say it could be adapted to detect a range of viruses that plague humans, including Ebola, Zika and HIV.

“The ultimate goal is to build a cheap, easy-to-use device to take into the field and measure the presence of a virus like Ebola in people on the spot,” says Jeffrey Dick, chemistry graduate student and co-lead author of the study. “While we are still pretty far from this, this work is a leap in the right direction.”

The new method is highly selective, meaning it is only sensitive to one type of virus, filtering out possible false negatives due to other viruses or contaminants.

There are two other commonly used methods for detecting viruses in biological samples, but they have drawbacks: one requires a much higher concentration of viruses and the other requires samples to be purified to remove contaminants. The new method, however, can be used with urine straight from a person or animal.

The other co-authors are Lauren Strawsine, a postdoctoral fellow in chemistry, Jason Upton, an assistant professor of molecular biosciences and Allen Bard, professor of chemistry and director of the Center for Electrochemistry.

The researchers demonstrated their new technique on a virus that belongs to the same family as the herpes virus, called murine cytomegalovirus (MCMV). To detect individual viruses, the team places an electrode–a wire that conducts electricity, in this case, one that is thinner than a human cell–in a sample of mouse urine. They then add to the urine some special molecules made up of enzymes and antibodies that naturally stick to the virus of interest. When all three stick together and then bump into the electrode, there’s a spike in electric current that can be easily detected.

The researchers say their new method still needs refinement. For example, the electrodes become less sensitive over time because a host of other naturally occurring compounds stick to them, leaving less surface area for viruses to interact with them. To be practical, the process will also need to be engineered into a compact and rugged device that can operate in a range of real world environments.

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https://www.sciencedaily.com/releases/2016/05/160523160443.htm Original web page at Science Daily

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Experimental drug against hepatitis C slows down Zika virus infection in mice

Virologists from KU Leuven, Belgium, have shown that an experimental antiviral drug against hepatitis C slows down the development of Zika in mice. The research team was led by Professor Johan Neyts from the Laboratory of Virology and Chemotherapy.

“The Zika virus is transmitted by the tiger mosquito. Roughly twenty percent of the people who are infected actually get sick,” explains Professor Neyts. “The most common symptoms, which last about a week, are fever, fatigue, joint and muscle pain, rash, and red eyes. A small number of infected people go on to develop Guillain-Barré Syndrome, which causes muscle weakness and temporary paralysis. In some cases, the patient needs to be put on a ventilator.”

“The biggest cause for concern is that pregnant women with the infection can pass on the virus to the fetus,” Neyts continues. “As a result, some babies are born with microcephaly, a disorder of the central nervous system whereby the child’s skull and brain are too small. In severe cases, these children grow up with serious physical and mental disabilities.”

Following explosive outbreaks of the virus on islands in the Pacific, the virus spread quickly to South and Central America and the Caribbean in 2015 and 2016. Earlier this year, the World Health Organisation declared the state of emergency to contain the epidemic as quickly as possible. After all, there is currently no vaccine or antiviral drug available to prevent or treat an infection.

“As the Zika virus is related to the hepatitis C virus, we examined whether some inhibitors of the hepatitis C virus also prevent the multiplication of the Zika virus in human cells. We have identified at least one experimental drug that is effective against the Zika virus.”

Next, the researchers needed to assess whether the inhibitor also provides protection in lab animals. “We used mice with a defect in their innate immune system. When these mice are infected with the Zika virus, they develop a number of the symptoms that we also see in human patients. Treating the infected mice with the hepatitis C virus inhibitor resulted in a clear delay in virus-induced symptoms.”

“The experimental hepatitis C inhibitor is not very powerful yet,” Neyts concludes. “Nevertheless, our study opens up important new possibilities. We can now start testing the effectiveness of other promising virus inhibitors and vaccines against the Zika virus.”

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https://www.sciencedaily.com/releases/2016/05/160517094212.htm Original web page at Science Daily

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Mouse models of Zika in pregnancy show how fetuses become infected

Two mouse models of Zika virus infection in pregnancy have been developed by a team of researchers at Washington University School of Medicine in St. Louis. In them, the virus migrated from the pregnant mouse’s bloodstream into the placenta, where it multiplied, then spread into the fetal circulation and infected the brains of the developing pups.

The models provide a basis to develop vaccines and treatments, and to study the biology of Zika virus infection in pregnancy. The research is published May 11 in Cell.

“This is the first demonstration in an animal model of in utero transmission of Zika virus, and it shows some of the same outcomes we’ve been seeing in women and infants,” said co-senior author Michael Diamond, MD, PhD, a professor of medicine, molecular microbiology and pathology and immunology. “This could be used in vaccine trials, to find out whether vaccinating the mother can protect against uterine infection. You also could test therapeutics, once the mother got infected, to see if they could arrest the transmission to the fetus or prevent damage to the fetus.”

Since mice with normal immune systems are able to fight off Zika infection, Diamond and colleagues weakened the mice’s immune systems before infecting them with the virus.

In one model, the researchers genetically modified mice to lack a molecule called interferon alpha receptor that plays a key role in the immune response to viral infections. In the other model, they injected mice with antibodies against the molecule.

The scientists infected pregnant mice with Zika virus about a week after conception and examined their placentas and fetuses six to nine days later. Both mouse models reflected some of the key aspects of human Zika infection. In the mice, as in humans, the virus crossed from the mother’s bloodstream into the fetus’s and infected the developing brain, where damage to neurons was observed.

Microcephaly — which is marked by abnormally small heads, the most striking result of human infection — was not observed in either model. This may be due to differences in how mouse and human brains develop.

“Unlike in humans, a significant amount of neurodevelopment in mice actually occurs after birth, especially in the cerebral cortex, which is the part of the brain damaged in microcephaly,” Diamond said.

Indira Mysorekar, PhD, co-senior author of the study and postdoctoral fellow Bin Cao, PhD, co-first author, found the virus in the placenta at 1,000 times the concentration in the maternal blood, suggesting that it had not just migrated to the placenta, but multiplied there.

In the genetically-modified mice, Zika infection caused the death of most of the fetuses, and the remaining fetuses were much smaller than normal. The placentas showed damage: They were shrunken, with a reduced number of blood vessels. Such placentas would be unable to supply enough oxygen and nutrients to a developing fetus, a condition known as placental insufficiency, which causes abnormally slow fetal growth and, in severe cases, fetal death.

Placental insufficiency, abnormally small fetuses and miscarriages have been reported in pregnant women infected with Zika virus, as well.

In both models, the virus also was detected in the fetal brain. The researchers observed cell death in the brains of infected fetuses, but there were no obvious abnormalities in the overall structure of the brain.

In the model in which mice were injected with antibodies, the effect of Zika infection was less severe. The fetuses survived, although some were smaller than normal. Diamond and colleagues plan to use this model to study whether prenatal Zika virus infection causes long-term neurological problems in pups born without obvious brain damage.

Not all babies born to women infected with Zika during pregnancy develop microcephaly; some seem healthy at birth. But it is unknown whether such babies will face developmental or intellectual challenges as they grow up.

Diamond and Mysorekar, an associate professor of obstetrics and gynecology, and of pathology and immunology, also want to identify the molecules the virus latches onto to get into and through the placenta, so they can block them. Zika’s greatest health threat is to developing fetuses; if that threat can be eliminated, the public health emergency would be significantly lessened.

“For years, we’ve been studying transplacental infections and what prevents them,” Mysorekar said. “It’s gratifying to be able to apply all that expertise to something that’s suddenly become very important around the world.”

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Zika virus may cause microcephaly by hijacking human immune molecule

The U.S. Centers for Disease Control and Prevention recently concluded that Zika virus infection in pregnant women can stunt neonatal brain development, leading to babies born with abnormally small heads, a condition known as microcephaly. Now, for the first time, researchers at University of California San Diego School of Medicine have determined one way Zika infection can damage developing brain cells. The study, published May 6, 2016 in Cell Stem Cell, also shows that inhibiting this mechanism reduces brain cell damage, hinting at a new therapeutic approach to mitigating the effects of prenatal Zika virus infection.

Using a 3D, stem cell-based model of a first-trimester human brain, the team discovered that Zika activates TLR3, a molecule human cells normally use to defend against invading viruses. In turn, hyper-activated TLR3 turns off genes that stem cells need to specialize into brain cells and turns on genes that trigger cell suicide. When the researchers inhibited TLR3, brain cell damage was reduced in this organoid model.

“We all have an innate immune system that evolved specifically to fight off viruses, but here the virus turns that very same defense mechanism against us,” said senior author Tariq Rana, PhD, professor of pediatrics at UC San Diego School of Medicine. “By activating TLR3, the Zika virus blocks genes that tell stem cells to develop into the various parts of the brain. The good news is that we have TLR3 inhibitors that can stop this from happening.”

In the study, Rana’s team first made sure their organoid model was truly representative of the early developing human brain. They found that the model’s stem cells differentiate (specialize) into the various cells of the brain in the same way that they do in the first trimester of human development. The researchers also compared patterns of gene activation in organoid cells to a database of human brain genetic information. They found that, genetically speaking, their organoid model closely resembled fetal brain tissue at eight to nine weeks post-conception.

When the team added a prototype Zika virus strain to the 3D brain model, the organoid shrank. Five days after the infection, healthy, mock-infected brain organoids had grown an average of 22.6 percent. In contrast, the Zika-infected organoids had decreased in size by an average 16 percent.

Rana’s team also noticed that the TLR3 gene was activated in the Zika virus-infected organoids. TLR3 is a protein found both inside and attached to the outside of cells. TLR3’s only job is to act as an antenna, sensing double-stranded RNA specific to viruses. When viral RNA binds TLR3, it kicks off an immune response. To do that, TLR3 helps activate many different genes that aid in fighting an infection. However, in developing brain cells, the researchers found TLR3 activation also influences 41 genes that add up to a double whammy in this model — diminished stem cell differentiation into brain cells and increased cell suicide, a carefully controlled process known as apoptosis.

To determine whether TLR3 activation could be the cause of Zika-induced organoid shrinkage — and therefore perhaps microcephaly — or merely a symptom of it, Rana’s team treated some of the infected organoids with a TLR3 inhibitor. They found that the TLR3 inhibitor significantly tempered Zika virus’ severe effects on brain cell health and organoid size, underscoring TLR3’s role linking infection and brain damage. However, the treated organoids weren’t perfect. As evidenced by their non-smooth outer surfaces, infected but treated organoids still encountered more cell death and disruption than uninfected organoids.

While promising, this research has been conducted only in human and mouse cells growing in the laboratory thus far. In addition, the Zika virus strain used in this study (MR766) originated in Uganda, while the current Zika outbreak in Latin America involves a slightly different strain that originated in Asia.

“We used this 3D model of early human brain development to help find one mechanism by which Zika virus causes microcephaly in developing fetuses,” Rana said, “but we anticipate that other researchers will now also use this same scalable, reproducible system to study other aspects of the infection and test potential therapeutics.”

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https://www.sciencedaily.com/releases/2016/05/160506132202.htm  Original web page at Science Daily

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A real Peter Rabbit tale: Biologists find key to myxoma virus/rabbit coevolution

A naturally-occurring mutation in a rabbit-specific virus — related to the smallpox virus — weakens the virus and may give insight to understanding pathogen evolution, according to a Kansas State University study.

“Our findings may help scientists predict which viruses can pose threats to humans,” said Stefan Rothenburg, assistant professor in the Division of Biology and principal investigator for the study. “It is a big step toward understanding the molecular basis of host-virus interaction.”

Rothenburg; microbiology doctoral students Chen Peng, China, and Sherry Haller, Topeka; and collaborators from the University of Florida, recently published a study in the Proceedings of the National Academy of Sciences of the United States of America about the function of an immune-regulating protein from myxoma virus, called M156. According to Rothenburg, M156 inhibits an antiviral protein from the host in a species-specific fashion. The researchers also characterized a loss-of-function mutation in M156 that makes the once severe virus weaker.

“We are still very ignorant when it comes to predicting which viruses pose threats to humans and animals,” Rothenburg said. “We don’t fully understand the molecular mechanisms. This is why it is important to study a very well established host-virus system like myxoma virus in the European rabbit as a model for human viruses and why understanding this mutation is important.”

Myxoma virus was intentionally released in Australia in the 1950s to control invasive rabbits. At that time, the mortality rate of virus infection was nearly 100 percent and the release led to a huge decrease in the European rabbit population. According to Rothenburg, within a few years, two things happened that stunned scientists at the time: Myxoma virus mutated to become weaker, or attenuated, and the rabbits evolved to become more resistant to the virus.

“These two phenomena together led to a rebound of the rabbit population,” Rothenburg said. “The scientists found that the naturally evolved weakening of the virus is actually beneficial for the virus because infected rabbits lived longer and were able to better transmit the virus.”

Rothenburg further said that on the population level, this is probably the best-known example for a host-virus coevolution in nature, but it lacked a molecular explanation until this study.

M156 normally inhibits a rabbit’s virus-defense factor called protein kinase R, or PKR. Peng and colleagues found that a single mutation causes the virus’s protein to fail at inhibiting the rabbit’s PKR and makes the virus weaker.

“The virus has an evolutionary advantage to maintain this mutation because it is found in more than 50 percent of the Australian virus isolates,” Peng said.

The researchers found that only rabbit PKR was inhibited by M156 but not PKR from other mammals, which may contribute to the reason why myxoma virus only causes disease in rabbits. According to Rothenburg, the interaction of the host and virus proteins is like a lock and a key where the lock is PKR and the virus inhibitor is the key. If either lock or key change, the virus cannot establish an active infection in the host, he said.

Rothenburg’s next step is to look at myxoma strains that were illegally released in Europe for the same purpose — to see if there are mutations in PKR inhibitors with similar effects. In addition, the Rothenburg lab is using the knowledge gained from the current study to modify myxoma virus with the goal to enhance the virus’s oncolytic activity and to expand the spectrum of cancer forms that can be destroyed by myxoma virus.

“Our findings are important because we can use the gained knowledge for examining pathogens that concern human health,” Rothenburg said. “Those include viruses such as influenza or Ebola viruses, which can jump from animals into the human population and also counteract their hosts’ immune system, including the inhibition of PKR. Investigating species-specific interactions might yield valuable information about which viruses pose future threats.”

https://www.sciencedaily.com/   Science Daily

https://www.sciencedaily.com/releases/2016/04/160405114754.htm  Original web page at Science Daily

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Developing ways to study influenza D virus

Although a new influenza virus, now called influenza D, was discovered first in pigs, researchers found it was more common in cattle. However, further research has identified antibodies to the virus in small ruminants, but not in poultry.

To identify exposure to the virus, South Dakota State University doctoral student Chithra Sreenivasan tests blood samples for influenza D antibodies. Working with the Minnesota Poultry Testing Lab, she found no evidence of the new influenza strain in poultry; however, she did find antibodies to the virus in sheep and goats from the Midwest through blood samples archived at Washington State University.

Sreenivasan co-authored a paper on those findings that was published in the international journal Veterinary Microbiology last year. In ongoing work, she and her colleagues have also identified antibodies in horses. For her work, she has received the Joseph P. Nelson Graduate Scholarship Award that recognizes original scientifc research.

“The virus has not been shown to be pathogenic in humans. No one should be afraid of this,” professor Radhey Kaushik said. SDSU alumnus Ben Hause, now a research assistant professor at Kansas State University, discovered the virus, which he identified and characterized as part of his doctoral work under tutelage of his research adviser, professor Feng Li.

Li and Kaushik secured a National Institutes of Health grant for nearly $400,000 to continue this work. Both faculty members have joint appointments in the biology and microbiology and veterinary and biomedical sciences departments at South Dakota State.

Ultimately, the goal is to determine whether the virus can cause problems in humans, he explained. “If the virus can undergo reassortment in combination with a closely related human influenza virus, it may be able to form a new strain that could pose more of a threat to humans.”

Using the bovine Influenza D strain, Sreenivasan proved that the guinea pig could be used as an animal model to study the virus. Though guinea pigs showed no symptoms, she successfully isolated antigens in tracheal and lung tissues. In addition, her research showed the virus is spread only through direct contact. Those results were published in the Journal of Virology, with Sreenivasan as the first author of the article.

Her current study uses the guinea pig model to compare virulence among bovine and swine Influenza D strains and human influenza C. She has just begun analyzing the data. Influenza D has about 50 percent similarity to human influenza C, Sreenivasan explained.

“Human C affects mostly children,” she said, noting that the most common symptom is a runny nose. “It’s not a serious disease. We all have some antibodies because we were infected as children.”

In addition, she is developing a way to study the virus in living cells — trachea and lung epithelial cells from swine and cattle. “I isolate the cells and allow them to grow and then infect them to study the genetic and biologic characteristics,” she said.

Thus far, she’s completed the swine cell cultures and will now begin work on bovine cells. Using the in vitro culturing system, Sreenivasan said, “We will see how the virus attaches and what the receptors are.”

https://www.sciencedaily.com/   Science Daily

https://www.sciencedaily.com/releases/2016/04/160408103351.htm Original web page at Science Daily

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* Canine influenza transmitted to cats in Midwestern shelter

It may be called canine influenza, but Sandra Newbury, clinical assistant professor and director of the Shelter Medicine Program at the University of Wisconsin School of Veterinary Medicine, has confirmed that the virus that sickened a large number of dogs in the Midwest last year has now infected a group of cats in the region.

Newbury, in collaboration with Kathy Toohey-Kurth, virology section head at the Wisconsin Veterinary Diagnostic Laboratory, recently tested multiple cats at an animal shelter in Northwest Indiana and found them positive for the H3N2 canine influenza virus.

“Suspicions of an outbreak in the cats were initially raised when a group of them displayed unusual signs of respiratory disease,” Newbury says. “While this first confirmed report of multiple cats testing positive for canine influenza in the U.S. shows the virus can affect cats, we hope that infections and illness in felines will continue to be quite rare.”

Feline cases previously reported in South Korea suggested that the virus — which was not seen in the U.S. until 2015 — was capable of making the leap from dogs to cats. However, just one cat tested positive for H3N2 on a single occasion in the U.S. last year. In that case, no repeated sampling was done because the sample was not known to be positive until long after the cat’s symptoms had resolved.

It now appears the virus can replicate and spread from cat to cat. “Sequential sampling of these individual cats have shown repeated positives and an increase in viral loads over time,” Toohey-Kurth says, referring to the amount of virus found in any given sample.

Preliminary work to study the genetic signature of the virus shows it to be identical to the H3N2 virus that infects dogs. Researchers at WVDL are currently completing a full genetic analysis and study of the virus.

Newbury and the UW Shelter Medicine team are working closely with the animal shelter to manage the influenza outbreak. A number of dogs at the shelter have also tested positive for the virus.

“At this time, all of the infected cats have been quarantined, and no infected cats or dogs have left this shelter,” Newbury says. “We will continue to watch carefully for instances of the disease.”

Cats that have contracted the virus in the shelter have displayed upper respiratory symptoms such as runny nose, congestion and general malaise, as well as lip smacking and excessive salivation. Symptoms have resolved quickly and so far, the virus has not been fatal in cats.

Infected dogs may develop a persistent cough, runny nose and fever. Some dogs will show no symptoms, while others exhibit more severe signs of illness. The virus has been linked to some deaths in dogs, but most dogs recover with supportive care.

Dogs and cats infected with canine influenza virus should be housed separately from other animals and precautions should be taken to prevent spread of the virus on hands and clothing.

An H3N2 vaccine is now available for dogs, but no vaccine is currently approved or recommended for cats. A veterinarian can recommend whether or not to seek an H3N2 canine influenza vaccine for dogs.

https://www.sciencedaily.com/   Science Daily

https://www.sciencedaily.com/releases/2016/04/160401080741.htm  Original web page at Science Daily

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Likely biological link found between Zika virus, microcephaly

Working with lab-grown human stem cells, a team of researchers suspect they have discovered how the Zika virus probably causes microcephaly in fetuses. The virus selectively infects cells that form the brain’s cortex, or outer layer, making them more likely to die and less likely to divide normally and make new brain cells.

The researchers say their experiments also suggest these highly-susceptible lab-grown cells could be used to screen for drugs that protect the cells or ease existing infections.

“Studies of fetuses and babies with the telltale small brains and heads of microcephaly in Zika-affected areas have found abnormalities in the cortex, and Zika virus has been found in the fetal tissue,” says Guo-li Ming, M.D., Ph.D., a professor of neurology, neuroscience, and psychiatry and behavioral science at Johns Hopkins’ Institute for Cell Engineering. “While this study doesn’t definitely prove that Zika virus causes microcephaly, it’s very telling that the cells that form the cortex are potentially susceptible to the virus, and their growth could be disrupted by the virus.” Ming led the research team along with Hongjun Song, Ph.D., a professor of neurology and neuroscience in the Institute for Cell Engineering, and Hengli Tang, Ph.D., a virologist at Florida State University.

Results of the experiments, conducted by researchers at the Johns Hopkins University School of Medicine, Florida State University, and Emory University, are described online March 4 in the journal Cell Stem Cell.

In a quickly executed study that reflects the global public health threat posed by Zika, the researchers compared Zika’s effect on cells known as cortical neural progenitor cells to two other cell types: induced pluripotent stem cells and immature neurons. Induced pluripotent stem cells are made by reprogramming mature cells, and can give rise to any cell type in the body, including cortical neural progenitor cells. Cortical neural progenitor cells in turn give rise to immature neurons.

The experiments, conducted in less than a month, began when Tang reached out to Ming and Song, who use stem cells to study early brain development. The Johns Hopkins labs sent team members and cells to Tang’s lab, where the cells were exposed to Zika virus. Then the cells’ genetic expression — evidence of which genes were being used by the cells and which weren’t — were analyzed in Peng Jin’s laboratory at Emory University.

According to Tang, three days after exposure to the virus, 90 percent of the cortical neural progenitor cells were infected, and had been hijacked to churn out new copies of the virus. Furthermore, the genes needed to fight viruses had still not been switched on, which is highly unusual, he adds. Many of the infected cells died, and others showed disrupted expression of genes that control cell division, indicating that new cells could not be made effectively.

Using specific, known types of cells allowed the researchers to see where the developing brain is most vulnerable, Song says. He and Ming are now using the cells to find out more about the effects of Zika infection on the developing cortex. “Now that we know cortical neural progenitor cells are the vulnerable cells, they can likely also be used to quickly screen potential new therapies for effectiveness,” Song adds.

Zika virus has recently emerged as a public health concern, but it was first discovered in Uganda in the 1940s. Since then, small outbreaks have appeared in Asia and Africa, but symptoms were generally mild and did not appear to have any long-term effects. Carried by infected Aedes aegypti mosquitos, Zika is largely transmitted through bites, but can also occur through intrauterine infection or sexual transmission.

In 2015, the Zika virus began spreading throughout the Americas and a potential link was seen between the virus and a significant increase in cases of fetal microcephaly, as well as other neurologic abnormalities. This connection and the proliferation in cases led to the World Health Organization declaring Zika virus an international public health emergency.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160304163404.htm  Original web page at Science Daily

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New virus transmission route discovered in pigs

Japanese Encephalitis (JE) virus causes serious inflammation of the brain in people and fertility problems in pigs. Mosquitoes were previously the only known transmission route. However, the virus can also be spread from pig to pig by direct contact, and this could enable it to circulate in pigs during the mosquito-free winter season.

The JE virus is the main cause of serious encephalitis in people in Asia. The virus is found in large parts of Southeast Asia and is now also widespread in India. It circulates between birds and mosquitoes and between pigs and mosquitoes, and is passed to humans through mosquito bites. In children in particular, infection can lead to acute encephalitis and permanent impairment or even death.

In pigs, the main effect of the virus alongside fever and encephalitis is fertility problems. The virus is closely related to the West Nile, Zika and dengue viruses. All are transmitted by mosquitoes and are flaviviruses, which cause serious illness in humans and animals.

Previously, the only known transmission route for JE viruses was mosquitoes. A team of researchers from the Institute of Virology and Immunology and the University Bern at the Vetsuisse Faculty led by Dr. Meret Ricklin and Prof Artur Summerfield have now shown that JE viruses can also be passed directly from pig to pig. The study has just been published in the journal “Nature Communications.”

Up to now, there had been no explanation for how the JE virus could survive over winter in regions such as the northern Japanese island of Hokkaido, and cause new outbreaks the following year. Outbreaks in some cases occurred on the same farms as in the previous year, despite the fact that no infected mosquitoes could be found in the area. In Taiwan, too, pigs were infected with JE viruses during the winter, but no infected mosquitoes found.

As the researchers have now been able to show, infected pigs discharge the virus in their saliva for several days, and the animals are also susceptible to infection through the mouth or nose with very low doses of the virus. In pigs — as in humans — the virus was found to spread through the brain and cause inflammation. The virus was, however, found to grow most in the tonsils, where it was detectable for several weeks or even months. The authors suggest that JE viruses could possibly circulate in pigs and survive for up to months. When the virus is secreted again, for example as a result of a different infection that weakens the immune system, a new infection cycle could then begin. However, the researchers say that further studies are needed to prove this link.

The study published shows that even for viruses that are spread by insect bites, direct transmission through animal to animal contact cannot be ruled out. “This means that the virus could circulate within the pig population without mosquitoes, and thus spread even to regions with a temperate climate,” says Artur Summerfield. This would theoretically also mean a higher risk to humans. A vaccine is, however, available for both people and animals. The virus has to date only occurred in Europe in travellers returning from Asia and in those cases did not lead to any further infections.

The Institute of Virology and Immunology (IVI) with sites at Mittelhäusern and Bern is the Swiss reference laboratory for the diagnosis, surveillance and control of highly infectious animal diseases. IVI is part of the Swiss Federal Food Safety and Veterinary Office (FSVO).

As part of cooperation with the Vetsuisse Faculty of the University of Bern, the IVI is responsible for teaching and research in the field of virology and immunology. Research activities include both basic and applied research, and provide an important basis for the control of animal diseases and zoonoses (infectious diseases that can be spread between humans and animals).

https://www.sciencedaily.com/   Science Daily

https://www.sciencedaily.com/releases/2016/02/160223074841.htm  Original web page at Science Daily

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Zika researchers release real-time data on viral infection study in monkeys

Researchers in the United States who have infected monkeys with Zika virus made their first data public last week.  But instead  of publishing them in a journal, they have released them online for anyone to view- and are updating their results day by day.

The team is posting raw data on the amount of virus detected in the blood, saliva and urine of three Indian rhesus macaques, which they injected with Zika on 15 February. “This is the first time Researchers in the United States who have infected monkeys with Zika virus made their first data public last week. But instead of publishing them in a journal, they have released them online for anyone to view — and are updating their results day by day.

that our group has made data available in real time,” says David O’Connor, a virologist at the University of Wisconsin–Madison and a leader of the project, whose scientists have dubbed themselves ZEST (the Zika experimental-science team). He hopes that releasing the data will help to speed up research into the nature of the virus that has spread across the Americas.

Although a few teams have begun to share genomic data online during disease outbreaks, instant open-data release remains the exception rather than the rule, particularly in clinical research. O’Connor says that he was inspired by researchers during the Ebola epidemic who rapidly published genomic-sequencing data online and encouraged others to re-analyse them. At the time, O’Connor’s group downloaded raw data shared by a team led by Pardis Sabeti, a computational geneticist at the Broad Institute and Harvard University in Cambridge, Massachusetts; it immediately helped to advance their own Ebola research, he says, and led to a collaboration with Sabeti’s group.

“O’Connor’s team is to be lauded for their efforts to make their Zika virus data publicly available as soon as possible,” says Nathan Yozwiak, a senior scientist in Sabeti’s laboratory. “Distributing up-to-date information — in this case, animal model data — as widely and openly as possible is critical during emergencies such as Zika, where relatively little is known about its pathogenesis, yet public concerns and attention are so high.”

“This is exemplary for research,” agrees Koen Van Rompay, a specialist in non-human primate models of HIV infection at the California National Primate Research Center at the University of California, Davis. Van Rompay is part of a consortium that plans to inject pregnant macaques with Zika. He says that his team will also share data openly in real time.

David O’Connor, whose ‘ZEST’ team at the University of Wisconsin-Madison are releasing Zika data in real time. O’Connor’s team seems to be the first to have detailed information from macaques infected with Zika virus, so the rapid data release will enable other researchers planning similar experiments to take the work into account, saving time and resources, Van Rompay adds. “This is such an urgent public-health emergency that this should not be a race of scientists competing against each other. We’re in a race against the Zika virus, a race against time,” he says.

Like other researchers, the ZEST team wants to understand when a developing fetus might be at risk of birth defects from Zika. Typically, the virus gives rise to no or mild symptoms — but scientists are urgently working to estimate the strength of any association between Zika infection and an apparent rise in the number of babies born with microcephaly (abnormally small heads and brains) in northeastern Brazil.

If the virus behaves the same way in macaques that it does in humans, O’Connor says, researchers will be able to glean information by infecting monkeys with varying doses of Zika — data that would be impossible to gain rapidly or ethically from people. Scientists could repeatedly sample amniotic fluid in pregnant macaques, for example, to determine whether, and how quickly, the virus can infect a fetus.

The team is starting with male monkeys to get information on how the virus behaves in macaques and determine which dose would be most suitable for later experiments. They have already shown that Zika can infect macaques and that it is detectable not only in blood, but also in cerebrospinal fluid and urine. They will follow up their work with experiments in macaques at different stages of pregnancy, checking for the virus’s presence in a wide range of tissues and organs.

Even if a link to birth defects is proven, it may still be that very few Zika infections during pregnancy lead to microcephaly, O’Connor says. But he thinks that even with a small number of animals, the team can assess important questions such as whether fetuses become infected with Zika virus and whether they develop abnormalities as a result.

Pregnant rhesus macaques have been used in past to study congenital birth defects, O’Connor adds. Research on the effects of cytomegalovirus or Listeria, for example, have revealed that the diseases produce similar effects in macaques and in humans. The team also hopes to carry out Zika studies in marmosets, which are native to northeastern Brazil and smaller than macaques, making them easier to work with in the lab. If it is possible for the virus to infect marmosets, this might also suggest that the animals are involved in Zika transmission in Brazil, O’Connor says.

It was easy for the ZEST members to make their online lab notebook open to all, O’Connor says. The team uses the biomedical-research collaboration system LabKey Server, as does the Wisconsin National Primate Research Center in Madison, which is where many of the ZEST collaborators work and which (along with the US National Institutes of Health) is supporting the research. Researchers created a study to store and update their data, and simply had to switch permissions to allow anyone to view it. Meanwhile, regulatory agencies at the University of Wisconsin–Madison understood that the work was time-sensitive and expedited approvals for animal care and biosafety (without reducing scrutiny, O’Connor adds).

On 10 February, dozens of major funders, government agencies and journals released a statement supporting open-data sharing — even before publication — during public-health emergencies such as the Zika and Ebola epidemic. “In the context of a public-health emergency of international concern, there is an imperative on all parties to make any information available that might have value in combatting the crisis,” it concluded.

Jeremy Farrar, director of the Wellcome Trust in London – one of the research funders that signed the statement – says he welcomes the “increasing commitment” of scientists to sharing information during public health emergencies. “The world is changing and all of us involved need to encourage, facilitate and give thanks and credit to these teams and the approach they are taking,” he says.

“I hope that even those who disagree in principle with animals in research realize that making data available publicly works towards a common goal,” O’Connor adds. “Fewer animals will be used in research if groups know what others are doing, and the information that is gained from each animal is maximized.”

Nature doi:10.1038/nature.2016.19438

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/zika-researchers-release-real-time-data-on-viral-infection-study-in-monkeys-1.19438  Original web page at Nature

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Zika virus linked to stillbirth, other symptoms in Brazil

In January, a pregnant Brazilian woman infected with the Zika virus had a stillborn baby who had signs of severe tissue swelling as well as central nervous system defects that caused near-complete loss of brain tissue. It is the first report to indicate a possible association of congenital Zika virus and damage to tissues outside the central nervous system, said Yale researchers.

The researchers — led by Albert Ko, M.D. at Yale School of Public Health (YSPH) and Dr. Antônio Raimundo de Almeida at the Hospital Geral Roberto Santos in Salvador, Brazil — describe the case in the journal PLOS Neglected Tropical Diseases.

Ko and colleagues said the case provides evidence that, in addition to microcephaly — a condition marked by an abnormally small head in newborns and widely linked to the Zika outbreak in Brazil — congenital Zika infection may also be linked to hydrops fetalis (abnormal accumulation of fluid in fetal compartments), hydranencephaly (almost complete loss of brain tissue), and fetal demise (stillbirth).

The researchers said that it is not possible to extrapolate from a single case the overall risk for these outcomes faced by women who are exposed to the virus during pregnancy.

“These findings raise concerns that the virus may cause severe damage to fetuses leading to stillbirths and may be associated with effects other than those seen in the central nervous system,” said Ko, chair of the Department of Epidemiology of Microbial Diseases at YSPH, who has worked on the Zika outbreak in the coastal city of Salvador with Brazilian colleagues since shortly after the first cases of the mosquito-borne virus were reported there in early 2015.

“Additional work is needed to understand if this is an isolated finding and to confirm whether Zika virus can actually cause hydrops fetalis,” he said.

The patient, a 20-year-old woman, was having a normal pregnancy during her first trimester. That changed abruptly during the course of the 18th week of pregnancy, when an ultrasound examination discovered that the fetus’ weight was well below where it should have been at that point.

The woman did not report any of the symptoms commonly associated with Zika (rash, fever, or body aches) prior to or during the early stages of her pregnancy, the researchers said. She also did not exhibit symptoms of other mosquito-borne diseases, including dengue or chikungunya.

By the 30th week of the pregnancy, the fetus showed a range of birth defects. Labor was induced at the 32nd week. Researchers subsequently confirmed the presence of the Zika virus in the fetus. The strain of Zika that was found appears to be the same strain that is currently spreading elsewhere.

Since Zika appeared in Brazil, the virus has spread rapidly throughout much of Latin America and into the Caribbean. Several cases have also been confirmed in the United States.

The researchers said that since it is likely that large numbers of pregnant women in Brazil and beyond will be exposed to the same Zika strain as the woman in the case study, further investigations are needed to determine the risk of stillbirth and the other adverse outcomes.

Ko worked on the study with colleagues from the Hospital Geral Roberto Santos in Salvador, the Universidade Federal da Bahia in Salvador, the Oswaldo Cruz Foundation in Salvador, and the University of Texas Medical Branch in Galveston.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/02/160225153403.htm  Original web page at Science Daily

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Experimental Ebola antibody protects monkeys

Scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues have discovered that a single monoclonal antibody–a protein that attacks viruses–isolated from a human Ebola virus disease survivor protected non-human primates when given as late as five days after lethal Ebola infection. The antibody can now advance to testing in humans as a potential treatment for Ebola virus disease. There are currently no licensed treatments for Ebola infection, which caused more than 11,000 deaths in the 2014-2015 outbreak in West Africa. The findings are described in two articles to be published online by Science on February 25.

NIAID researchers obtained and tested blood samples from a survivor of the 1995 Ebola outbreak in Kikwit, Democratic Republic of the Congo, and discovered the survivor retained antibodies against Ebola. Investigators from the Institute for Research in Biomedicine in Switzerland then isolated specific antibodies for potential use as a therapeutic for Ebola infection. Investigators from the United States Army Medical Research Institute of Infectious Diseases administered a lethal dose of Zaire ebolavirus to four rhesus macaques, waited five days, and then treated three of the macaques with daily intravenous injections of the monoclonal antibody, known as mAb114, for three consecutive days. The untreated control macaque showed indicators of Ebola virus disease and died on day nine, but the treatment group survived and remained free of Ebola symptoms.

NIAID and Dartmouth College researchers then studied how mAb114 neutralizes the Ebola virus and determined that it binds to the core of the Ebola glycoprotein, blocking its interaction with a receptor on human cells. This area of the Ebola glycoprotein, called the receptor binding domain, was previously thought to be unreachable by antibodies because it is well-hidden by other parts of the virus, and only becomes exposed after the virus enters the inside of cells. This is the first antibody to demonstrate the ability to neutralize the virus by this interaction between the virus and its cellular receptor. Together the evidence identifies a novel site of vulnerability on the Ebola virus and suggests mAb114 could be an effective therapy and warrants further exploration, according to the authors.

https://www.sciencedaily.com   Science Daily

https://www.sciencedaily.com/releases/2016/02/160225153427.htm  Original web page at Science Daily

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* Electron microscopy captures snapshot of structure coronaviruses use to enter cells

High-resolution cryo-electron microscopy and supercomputing have now made it possible to analyze in detail the infection mechanisms of coronaviruses. These viruses are notorious for attacking the respiratory tract of humans and animals.

A research team that included scientists from the University of Washington (UW), the Pasteur Institute and the University of Utrecht has obtained an atomic model of a coronavirus spike protein that promotes entry into cells. Analysis of the model is providing ideas for specific vaccine strategies. The study results are outlined in a recent UW Medicine-led study published in Nature. David Veesler, UW assistant professor of biochemistry, headed the project.

These viruses, with their crowns of spikes, are responsible for almost a third of mild, cold-like symptoms and atypical pneumonia worldwide, Veesler explained. But deadly forms of coronaviruses emerged in the form of SARS-CoV (severe acute respiratory syndrome coronavirus) in 2002 and of MERS-CoV (Middle East respiratory syndrome coronavirus) in 2012 with fatality rates between 10 percent to 37 percent.

These outbreaks of deadly pneumonia showed that coronaviruses can transmit from various animals to people. Currently, only six coronaviruses are known to infect people, but many coronaviruses naturally infect animals. The recent deadly outbreaks resulted from coronaviruses overcoming the species barrier. This suggests that other new, emerging coronavirus with pandemic potential are likely to emerge. There are no approved vaccines or antiviral treatments against SARS-CoV or MERS-CoV.

The ability of coronaviruses to attach to and enter specific cells is mediated by a transmembrane spike glycoprotein. It forms trimers decorating the virus surface. Trimers are structures assembled from three identical protein units. The structure the researchers studied is in charge of binding to and fusing with the membrane of a living cell. The spike determines what kinds of animals and what types of cells in their bodies each coronavirus can infect.

Using state of the art, single particle cryo-electron microscopy and supercomputing analysis, Veesler and his colleagues revealed the architecture of a mouse coronavirus spike glycoprotein trimer. They uncovered an unprecedented level of detail. The resolution is 4 angstroms, a unit of measurement that expresses the size of atoms and the distances between them and that is equivalent to one-tenth of a nanometer.

“The structure is maintained in its pre-fusion state, and then undergoes major rearrangements to trigger fusion of the viral and host membranes and initiate infection,” Veesler explained.

The coronavirus fusion machinery is reminiscent of the fusion proteins found in another family of viruses, the paramyxoviruses, which include respiratory syncytial virus (the leading cause of infant hospitalizations and wheezing in children) as well as the viruses that cause measles and mumps. This resemblance implies that the coronavirus and paramyxovirus fusion proteins could employ similar mechanisms to promote viral entry and share a common evolutionary origin.

The researchers also compared crystal structures of parts of the spike protein in mouse and human coronaviruses. Their findings provide clues as to how the molecular structure of these protein domains might influence which specific animal species the virus is able to infect.

The researchers also analyzed the structure for possible targets for vaccine design and anti-viral therapies. They observed that the outer edge of the coronavirus spike trimer has a fusion peptide — a chain of amino acids — that is involved in viral entry into host cells. The easy accessibility of this peptide, and its expected similarity among a number of coronaviruses, suggests possible vaccine strategies to neutralize a variety of these viruses.

“Our studies revealed a weakness in this family of viruses that may be an ideal target for neutralizing coronaviruses,” Veesler said.

There may be a way, the researchers noted, to elicit broadly neutralizing antibodies recognizing this peripheral peptide. Neutralizing antibodies protect against infections by stopping a mechanism in a pathogen. Broadly neutralizing antibodies would be effective against several strains of pathogen, in this case coronaviruses. The physical structure of the fusion peptide inspires ideas for the design of proteins that would disable it.

“Small molecules or protein scaffolds might eventually be designed to bind to this site,” Veesler said, “to hinder insertion of the fusion peptide into the host cell membrane and to prevent it from undergoing changes conducive to fusion with the host cell. We hope that this might be the case, but much more work needs to be done to see if it is possible.”

The coronavirus spike protein structure described in this Letter to Nature is expected to resemble other coronavirus spike proteins.

“Therefore, the structure we analyzed in the mouse coronavirus is likely to be representative of the architecture of other coronavirus spike proteins such as those of MERS-CoV and SARS-CoV,” the researchers observed.

The researchers summed up their paper, “Our results now provide a framework to understand coronavirus entry and suggest ways for preventing or treating future coronavirus outbreaks.”

“Such strategies,” Veesler said, “would be applicable to several existing coronaviruses and to emerging future strains of coronavirus that conserve this same structure for entering cells.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/02/160226173209.htm  Original web page at Science Daily

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* Zika virus might cause Guillain-Barré syndrome, according to new evidence

Analysis of blood samples from 42 patients diagnosed with Guillain-Barré syndrome (GBS) during the Zika virus outbreak in French Polynesia provides the first evidence that Zika virus might cause GBS, a severe neurological disorder, according to new research published in The Lancet today. Based on the analysis of data from French Polynesia, if 100000 people were infected with Zika virus, 24 would develop GBS.

“This is the first study to look at a large number of patients who developed Guillain-Barré syndrome following Zika virus infection and provide evidence that Zika virus can cause GBS,” says lead author Professor Arnaud Fontanet from the Institut Pasteur, Paris, France. “Most of the patients with GBS reported they had experienced symptoms of Zika virus infection on average 6 days before any neurological symptoms, and all carried Zika virus antibodies.”

In between October 2013 to April 2014, French Polynesia experienced the largest Zika outbreak to be reported at the time. An estimated 32000 patients consulted a doctor about a suspected Zika virus infection, and 42 patients were diagnosed with GBS between November 2013 and February 2014. Zika virus infection is associated with symptoms such as fever, rash, joint and muscle pain and conjunctivitis. The current Zika outbreak in Central and South America was followed by increased reports of cases of microcephaly and GBS, leading the World Health Organisation to declare it a global emergency.

Guillain-Barré syndrome (GBS) is a disorder which affects the immune and nervous systems, and is the leading cause of non-trauma related paralysis. Symptoms develop rapidly and include weakness in the legs and arms, muscle weakness and pain. In about 20-30% of cases, severe GBS can lead to respiratory failure, and about 5% of patients die. GBS is usually triggered by an infection and can sometimes develop following infections of herpes, influenza or dengue virus. Across Europe and North America, GBS affects approximately 1-2 people out of 100000 per year.

The aim of the study was to determine the link between Zika virus infection and GBS. Since French Polynesia is also prone to outbreaks of dengue virus, the researchers also wanted to see whether dengue virus was an additional risk factor for GBS.

All 42 patients with GBS diagnosed at the Centre Hospitalier de Polynésie Française in Papeete, Tahiti were included in the study. Researchers recruited two control groups. The first control group (CTR 1), matched for age, gender and island of residence, consisted of 98 patients who attended the same hospital but did not have a fever. The second control group (CTR 2) consisted of 70 patients who tested positive for Zika virus infection, but did not develop any of the neurological symptoms associated with GBS. Blood samples were collected from all patients.

Most (88%) of the patients with GBS reported symptoms of Zika virus infection approximately 6 days before the onset of neurological symptoms. While none tested positive for a Zika virus infection once in hospital, blood tests showed that 41 (98%) were carrying Zika virus antibodies, and all (100%) had neutralizing antibodies against Zika virus.

By comparison, only 54 (56%) of the patients without a fever (CTR 1 group) were carrying Zika virus neutralizing antibodies. Most patients with GBS (95.2%) had signs of past dengue virus infection, as did most patients in the two control groups (88.8% in CTL 1; 82.9% in CTL 2). The authors therefore concluded that, in this case, past infection with dengue virus did not increase the risk of GBS among patients infected with Zika virus.

All 42 patients were diagnosed with a type of GBS called ‘acute-motor axonal neuropathy’ (AMAN), but few carried the biological markers typically associated with AMAN, suggesting a previously unknown disease mechanism. The patients in the study generally recovered faster than is usually expected with GBS.

Of the 42 patients with GBS, 16 (38%) were admitted to the hospital’s intensive care unit and 12 (29%) required breathing assistance. On average, patients were hospitalised for 11 days, but those in intensive care remained for longer (51 days). Three months after discharge, 24 (57%) patients were able to walk without assistance. No patients with GBS died.

Based on an attack rate for Zika virus of 66% in French Polynesia, the authors estimate that the risk of Guillain-Barré syndrome in the general population during the outbreak in French Polynesia is 0·24 per 1000 Zika virus infections (or 24 people per 100000 infections).

Professor Fontanet adds: “Although it is unknown whether attack rates of Zika virus epidemics will be as high in affected regions in Latin America than in the Pacific Islands, high numbers of cases of Guillain-Barré syndrome might be expected in the coming months as the result of this association. The results of our study support that Zika virus should be added to the list of infectious pathogens susceptible to cause Guillain-Barré syndrome.”

Writing in a linked Comment, Professor David W Smith, University of Western Australia, Australia says: “A little caution should be taken because the data are still scarce and we do not know whether the current Zika virus is identical to that in previous outbreaks, whether it will behave exactly the same in a different population with a different genetic and immunity background, or whether a cofactor or co-infection is responsible. Suffice to say Zika virus can be added to our list of viruses that can cause Guillain-Barré syndrome, and investigation of these cases should include tests for Zika when there is a possibility of infection by that virus. Whether Zika will be proven to pose a greater threat in causing Guillain-Barré syndrome than its various flavivirus cousins remains to be determined.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160301075119.htm  Original web page at Science Daily

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Effectiveness of a herpesvirus CMV-based vaccine against Ebola

This study represents a crucial step in the translation of herpesvirus-based Ebola virus vaccines into humans and other great apes. As the latest in a series of studies, researchers at Plymouth University, National Institutes of Health and University of California, Riverside, have shown the ability of a vaccine vector based on a common herpesvirus called cytomegalovirus (CMV) expressing Ebola virus glycoprotein (GP), to provide protection against Ebola virus in the experimental rhesus macaque, non-human primate (NHP) model. Demonstration of protection in the NHP model is regarded as a critical step before translation of Ebola virus vaccines into humans and other great apes.

The study is published Monday 15th February, in the online journal from Nature publishing, Scientific Reports.

In addition to establishing the potential for CMV-based vaccines against Ebola virus, these results are exciting from the potential insight they give into the mechanism of protection. Herpesvirus-based vaccines can theoretically be made to produce their targeted protein (in this case, Ebola virus GP) at different times following vaccination. The current CMV vaccine was designed to make the Ebola virus GP at later times. This resulted in the surprising production of high levels of antibodies against Ebola virus with no detectable Ebola-specific T cells. This immunological shift towards antibodies has never been seen before for such primate herpesvirus-based vaccines, where responses are always associated with large T cell responses and poor to no antibodies.

“This finding was complete serendipity,” says Dr Michael Jarvis who is leading the project at Plymouth University. “Although we will definitely need to explore this finding further, it suggests that we may be able to bias immunity towards either antibodies or T cells based on the time of target antigen production. This is exciting not just for Ebola, but for vaccination against other infectious as well as non-infectious diseases.”

A largely untold story is the devastating effect Ebola virus is having on wild great ape populations in Africa. Although the present study administered the vaccine by direct inoculation, a CMV-based vaccine that can spread from animal to animal may be one approach to protect such inaccessible wild animal populations that are not amenable to vaccination by conventional approaches. The current study is a step forward, not only for conventional Ebola virus vaccines for use in humans, but also in the development of such ‘self-disseminating vaccines’ to target Ebola in great apes, and other emerging infectious diseases in their wild animal host before they fully establish themselves in humans.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/02/160215090143.htm  Original web page at Science Daily