Researchers from the Gladstone Institutes have revealed that HIV does not cause AIDS by the virus's direct effect on the host's immune cells, but rather through the cells' lethal influence on one another.

HIV can either be spread through free-floating virus that directly infect the host immune cells or an infected cell can pass the virus to an uninfected cell. The second method, cell to cell transmission, is 100 to 1000 times more efficient, and the new study shows that it is only this method that sets off a cellular chain reaction that ends in the newly infected cells committing suicide.
"The fundamental 'killing units' of CD4 T cells in lymphoid tissues are other infected cells, not the free virus," says co-first author Gilad Doitsh, PhD, a staff research investigator at the Gladstone Institute of Virology and Immunology. "And cell-to-cell transmission of HIV is required for activation of the main HIV death pathway."
In a previous investigation, the scientists discovered that 95% of cell death from HIV is caused by immune cells committing suicide in self-defense after an unsuccessful infection. When the virus tries to invade a cell that is "at rest," the infection is aborted. However, fragments of viral DNA remain and are detected by the resting host cell. This triggers a domino effect in the cell's defense system, resulting in the activation of the enzyme caspase-1, which ultimately causes the induction of pyroptosis, a fiery form of cell suicide.
In the new study, published in Cell Reports, it was revealed that this death pathway is only activated through cell-to-cell transmission of HIV, not from infection by free-floating viral particles. Using lymphoid tissue infected with HIV, the scientists compared cell death rates between cell-to-cell and cell-free virus transfer. They discovered that while overall rates of infection remained the same, there was significantly more CD4 T cell death if HIV was spread by infection from other cells than by free-floating virus.
"Although free-floating viruses establish the initial infection, it is the subsequent cell-to-cell spread of HIV that causes massive CD4 T cell death," says co-first author Nicole Galloway, PhD, a post-doctoral fellow at the Gladstone Institute of Virology and Immunology. "Cell-to-cell transmission of HIV is absolutely required for activation of the pathogenic HIV cell-death pathway."
To confirm this finding, the researchers perturbed viral transfer through a number of means: genetically modifying the virus, applying chemical HIV inhibitors, blocking inter-cellular synapses, and increasing the physical distance between the cells so they could not come into contact with one another. Notably, disruption of cell-to-cell contact effectively stopped the death of CD4 T cells. What's more, only during cell-to-cell transmission was caspase-1 activated within the target cells, thereby initiating pyroptosis, the pro-inflammatory cell-suicide response.
The scientists speculate that the difference in cell death rates between the two methods of infection is due to the increased efficiency of cell-to-cell transmission. Aborted viral DNA fragments are quickly removed during infection by cell-free HIV particles, so they are not detected by the cell's defensive system. However, in cell-to-cell transmission, the viral DNA fragments overwhelm cell maintenance, building up until they surpass a threshold and are detected. This then triggers caspase-1 activation and pyroptosis.
"This study fundamentally changes our mindset about how HIV causes massive cell death, and puts the spotlight squarely on the infected cells in lymphoid tissues rather than the free virus," says senior author Warner C. Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology. "By preventing cell-to-cell transmission, we may able to block the death pathway and stop the progression from HIV infection to AIDS."
Other investigators on the study include Kathryn Monroe, Zhiyuan Yang, and Isa Muñoz-Arias from the Gladstone Institutes, and David Levy from New York University College of Dentistry. Funding was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases, the UCSF/Robert John Sabo Trust Award, and the Giannini Foundation Postdoctoral Research Fellowship.

Story Source:
The above post is reprinted from materials provided by Gladstone InstitutesNote: Materials may be edited for content and length.

Journal Reference:
  1. Nicole L. Galloway, Gilad Doitsh, Kathryn M. Monroe, Zhiyuan Yang, Isa Muñoz-Arias, David N. Levy, Warner C. Greene. Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T CellsCell Reports, 2015 DOI:10.1016/j.celrep.2015.08.011
Researchers have developed new insight into a rare but deadly brain infection, called progressive multifocal leukoencephalopathy (PML). This disease – which is caused by the JC virus – is most frequently found in people with suppressed immune systems and, until now, scientists have had no effective way to study it or test new treatments.


 “The JC virus is an example of an infection that specifically targets glia, the brain’s support cells,” said neurologist Steve Goldman, M.D., Ph.D., co-director of University of Rochester Center for Translational Neuromedicine and senior author of the paper. “Because this virus only infects human glia and not brain cells in other species, it has eluded our efforts to better understand this disease. To get around this problem, we have developed a new mouse model that allows us to study human glia in live animals.”
The JC virus is so common that it is estimated that 70 to 90 percent of all Americans have been exposed to it, and may carry it in a dormant form. For the vast majority of these people, the virus will never become infective or trigger any disease in their lifetimes. 
However, in some individuals with compromised immune systems – either because of a disease or from taking immunosuppressive drugs – the virus can become active and eventually make its way into the brain. Once there, the virus can trigger PML, an almost uniformly fatal infection of the white matter of the brain.
PML was first seen in leukemia and lymphoma patients in the 1950’s and 1960’s, but became more common during the AIDS epidemic in the 1980’s, prior to the widespread use of antiretroviral treatments. More recently, it has been increasingly observed in individuals undergoing long-term immunosuppressive treatments for autoimmune diseases like multiple sclerosis. 
Until now, it has been almost impossible to study the progression of disease or test new therapies, because the virus only attacks a specific human brain cell type called glia. It does not affect glia cells in mice or in any other animals commonly used to investigate disease mechanisms, making its study difficult.
Glia consists of two main categories of cells: astrocytes, the brain’s primary support cells, and oligodendrocytes, the source of myelin, the fatty tissue of the white matter that insulates nerve fibers in the brain. 
The new discovery – which appears today in the Journal of Clinical Investigation – was the result of research using a new tool developed at the University of Rochester. Last year, Goldman and Maiken Nedergaard, M.D., D.M.Sc., reported that they had created a mouse model whose brains consisted of both animal neurons and human glia cells. While the previous study focused on the fact that the human cells essentially made the mice smarter, at the same time it created a powerful new platform for researchers to study human glial cells in live adult animals, including diseases that impact these cells.
Previously, scientists believed that the JC virus attacked and killed oligodendrocytes, thereby destroying the brain’s ability to produce myelin. This conclusion had been reached because autopsies and MRI scans of people with PML revealed loss of the brain’s white matter, which is primarily comprised of myelin.
Using the new animal model, Goldman and his team were able to track the impact of the JC virus infection as it unfolded in real time. They observed that the initial target of the virus was, in fact, astrocytes and, to a lesser extent, glial progenitor cells, the cells that give rise to astrocytes and oligodendrocytes. The astrocytes serve as hosts for the virus to replicate and mutate, to the point where the cells literally explode and spread the infection in a chain reaction-like pattern.
Because astrocytes play an important support role, as they die off other cells – including oligodendrocytes – are affected. The virus does eventually infect and kill oligodendrocytes once the viral load in the brain reaches a tipping point, but these cells are not responsible for spreading the disease in the brain. Once oligodendrocytes begin to die off, myelin is lost, and since glial progenitor cells are also targeted by the virus, the brain loses its ability to replenish the lost myelin.
“We have been looking at the wrong cell population,” said Goldman. “Astrocytes seem to be the main target of the virus, and oligodendrocytes are essentially innocent bystanders caught in the crossfire.” 
These findings now enable researchers to focus on potential new ways to identify the early symptoms of the disease, as well as to develop new therapies. For example, patients who develop PML often complain of confusion and other cognitive problems, long before white matter loss prompts a clinical diagnosis. Goldman speculates that this may be the result of the early loss of astrocytes, which are known to help coordinate signal transmission in the brain. The new mouse model also allows researchers to test new therapies that specifically target infected astrocytes, while protecting their uninfected neighbors.
Additional authors include the paper’s two lead authors, Yoichi Kondo, Martha Windrem, as well as Lisa Zhou, Devin Chandler-Militello, Steven Schanz, Romane Auvergne, Sarah Betstadt, Amy Harrington, and Mahlon Johnson with the University of Rochester, and Alexander Kazarov and Leonid Gorelik with Biogen Idec. The study received support from the National Institute of Neurological Disorders and Stroke, the New York State Stem Cell Research Program, Biogen Idec, the University of Copenhagen, and the Novo Nordisk Foundation.
The secret to stopping a deadly stomach virus may be sitting right there in our guts, scientists reported Thursday in the journal Science. Or more specifically, the treatment is in our microbiome — the trillions of bacteria that inconspicuously hang out in the GI tracts.

Immunologists at Georgia State University found that a tiny piece of gut bacteria can prevent and cure a rotavirus infection in mice.

Of course, humans aren't mice. So the findings need to be taken with a grain of salt — and tested in people.
The study suggests a whole new benefit of the microbiome: to fight off viruses, says Lora Hooper, an immunologist at the University of Texas Southwestern Medical Center, who wasn't involved in the study. "It's tremendously important work," she says.
"But it's the first study, I'm aware of, showing that gut bacteria can trigger the immune system to protect against a virus," Hooper says. "And rotavirus is a bad one."
Anyone who has had a bad bout of food poisoning has a good idea about how nasty rotavirus can be — projectile vomiting, painful cramping and watery diarrhea for up to a week. It's not fun.
For young children in poor countries, rotavirus is one of the most deadly diseases. More than a half-million children under age 5 die from it each year.
There are two vaccines for the virus. They work well in the U.S. But so far, they haven't been very effective in many places where they're needed the most — India, sub-Saharan Africa and parts of Asia. (Genetic variation may be one reason for the discrepancy.)
Immunologist Andrew Gewirtz, who led the study, hopes the bacteria protein from the gut will one day be used to treat rotavirus outbreaks in developing countries — although that's still quite a long way off. But he says the findings also change how we think about the immune system more broadly.
"We were very, very surprised that a bacteria component offered powerful protection against a viral infection," Gewirtz says. "The basic thinking before was that bacteria have certain components on their surface that activate the immune system to fight bacteria, not viruses."
His team has some evidence that the bacteria protein may protect against other viruses, such as influenza — "although it doesn't work as well on flu as [on] rotavirus," Gewirtz says.
So what is this magic antiviral bullet?
It's those hairlike threads that dangle off some bacteria and help them swim. Yup, that's right, the flagella.
When Gewirtz and his team injected pieces of the flagella under the mice's skin, a part of the immune system kicked into action and stopped the rotavirus infection dead in its tracks.
But these bacteria — and their flagella — are in our gut. Would they still be able to talk to the immune system? Hooper thinks so. Here's why.
Just like our hair, flagella are constantly falling off the surfaces of bacteria as they swim around in the gut. "Cool immune cells, called dendritic cells, are constantly surveying what's going on in the body," Hooper says. They can bind to the pieces of flagella in the gut and then mobilize other immune cells to come and fight the viral infection.
"If this holds true in people," Hooper says, "it would make me think twice about taking antibiotics. Not only are they going to screw around with your gut bacteria, but they may make you more susceptible to viruses."
Museum biological collections are the records of life on Earth and as such, they are frequently used to investigate serious environmental issues. When public health officials were concerned about the levels of mercury in fish and birds, for example, scientists studied museum specimens to assess historical changes in mercury contamination. Eggs in museum collections were analyzed to establish the connection between DDT, thinning eggshells, and the decline in bird populations. And now, specimens from the Natural History Museum of Los Angeles County (NHM) have helped explain the mysteriously sudden appearance of a disease that has decimated sea stars on the North American Pacific Coast.



In a paper published Monday, November 17, 2014 in the journal Proceedings of the National Academy of Sciences, Cornell University microbiologist Ian Hewson and colleagues identify the Sea Star Associated Densovirus (SSaDV) virus as the microbe responsible for Sea Star Wasting Disease (SSWD). NHM Curator of Echinoderms Gordon Hendler and Collections Manager Cathy Groves, along with scientists from universities and aquariums along the coast (including NHM neighbor, the California Science Center), collaborated in the study.
Since June 2013, the largest die-off of sea stars ever recorded has swept the Pacific Coast. At least 20 different species of sea stars have been affected -- including iconic species like the "ochre star" and the multi-armed "sunflower star" -- and many populations of sea stars from Southern Alaska to Baja California have already disappeared.
Their large-scale disappearance is anticipated to have a serious and long-lasting ecological impact on coastal habitats, because sea stars are voracious predators, with a key role in regulating the ecology of the ocean floor.
Museum samples prove that the virus has existed at a low level for at least the past 72 years -- it was detected in preserved sea stars collected in 1942, 1980, 1987, and 1991. The study suggests the disease may have recently risen to epidemic levels because of sea star overpopulation, environmental changes, or mutation of the virus.
The study detected the virus on particles suspended in seawater, as well as in sediment, and showed that it is harbored in animals related to sea stars, such as sea urchins and brittle stars. Likely it can be transported by ocean currents, accounting for its rapid, widespread dispersal in the wild. Since the die-off began, the disease has caused a mass mortality of captive sea stars in aquariums on the Pacific Coast, although it did not spread in aquariums that sterilize inflowing seawater with UV light.
"There are 10 million viruses in a drop of seawater, so discovering the virus associated with a marine disease can be like looking for a needle in a haystack," Hewson said. In fact, the densovirus is the first and only virus identified in sea stars. However, its discovery will enable scientists to study how the virus infects sea stars and trace it in the ocean. Further research could reveal how the virus invades its host, why kills some sea stars, and why other species are unaffected.
Research might also identify factors that triggered the ongoing plague and help to predict or forestall similar events in the future.
"A recent publication highlighted examples of innovative studies for which museum time-series were integral in identifying responses to environmental change and bemoaned general decline in the growth of museum collections," said NHM's Hendler. "Fortunately, we bucked the trend and intentionally collected common, local species of sea stars, which made it possible to detect SSaDV in specimens from NHM!"

Story Source:
The above story is based on materials provided by Natural History Museum of Los Angeles CountyNote: Materials may be edited for content and length.

Journal Reference:
  1. Ian Hewson, Jason B. Button, Brent M. Gudenkauf, Benjamin Miner, Alisa L. Newton, Joseph K. Gaydos, Janna Wynne, Cathy L. Groves, Gordon Hendler, Michael Murray, Steven Fradkin, Mya Breitbart, Elizabeth Fahsbender, Kevin D. Lafferty, A. Marm Kilpatrick, C. Melissa Miner, Peter Raimondi, Lesanna Lahner, Carolyn S. Friedman, Stephen Daniels, Martin Haulena, Jeffrey Marliave, Colleen A. Burge, Morgan E. Eisenlord, and C. Drew Harvell. Densovirus associated with sea-star wasting disease and mass mortalityPNAS, November 17, 2014 DOI:10.1073/pnas.1416625111
Alternaria and other demaziacee normally not change the DTM agar plates colour. This Alternaria isolated into Mycology Laboratory in Policlinic "G. Martino" - University of Messina, change the color on DTM agar.


Presence of Gram-positive, partially acid-fast rods, which have grown in branching chains resembling fungal hyphae. (Gram stain; original magnification, ×100). Image courtesy MicrobeWorld user Kyriakos Zaragkoulias, Specialty Registrar (StR) in Medical Microbiology at General Hospital of Thessaloniki “G. Papanikolaou”, Greece.


Slime production by Staphylococcus epidermidis on Congo Red agar; demonstrated by black colored colonies. Slime production is one of the most important virulence factors produced by Coagulase negative Staphylococci. 

The colonies of slime non-producing strains remain pink to red. 




Unknown fungal isolated contaminant found on MAC. MAC plate was incubated for 2 months at 4 degrees C once fungal growth was seen. This colony seemed to emerge from the agar and had a 3D appearance. The center of the colony had what seemed to be hyphal growth while the edges had a hard waxy undulating apperance with a brown/amber color. The single colony was ~10 mm



A pink-pigmented strain of Pseudomonas aeruginosa is shown in the picture. This was photographed in University of Colorado Hospital's clinical lab by the microbiology department. The organism is shown on Mueller-Hinton agar for Kirby-Bauer sensitivity testing.

The pigment pyorubin is responsible for the vibrant red-to-pink color, and is produced by many Pseudomonas species. Pyorubin is also believed to be involved in protection of the organism against oxidative stress.




Many other pigments are produced by P. aeruginosa. The most commonly seen and expressed is pyocyanin, which gives P. aeruginosa its characteristic blue-to-green color. Pyocyanin has been determined to display antibiotic, antifungal and cytotoxic properties. It therefore is thought to contribute to the P. aeruginosa's pathogenesis. 

Pyoverdin is also produced by P. aeruginosa and is responsible for the fluorescent qualities of the organism. Pyoverdin is another virulance factor and acts as a siderophore, involved in a complex iron acquisition system, and has been determined to be an essential component in the formation of biofilms. 

Another less commonly seen pigment is pyomelanin, which gives P. aeruginosa a brown color.


Reference: Ferguson D., Cahill O.J., Quilty B. (2007). "Phenotypic, molecular and antibiotic resistance profiling of nosocomial Pseudomonas aeruginosa strains isolated from two Irish Hospitals." Journal of Medical and Biological Sciences 1:1.
Growth of Streptococcus mitis on blood agar demonstrating alpha hemolysis seen as a greenish color around the growing colonies due to a reduction of the hemoglobin to methemoglobin in the surrounding agar. Image taken using transmitted light. Image courtesy MicrobeWorld user Tasha Sturm, Cabrillo College.



 
Source:

Michigan Technological University
Summary:
If natural or human made disaster strikes, causing global crop failures, the world won't starve -- providing they are willing to eat bacterial slime and bugs. "People have been doing catastrophic risk research for a while. But most of what's been done is dark, apocalyptic and dismal. It hasn't provided any real solutions," says the author of a new book that provides a more optimistic outlook
 
 
 

 
 
"People have been doing catastrophic risk research for a while," says Pearce. "But most of what's been done is dark, apocalyptic and dismal. It hasn't provided any real solutions."
Even when looking at doomsday scenarios -- like super-volcanoes, abrupt climate change and nuclear winter -- society's forecast isn't horrific. In fact, Pearce says life will still have a sunny outlook. His research is outlined in a new book, Feeding Everyone No Matter What, out this week.
Survivalist Solution
"We researched the worst cases and asked, 'is it possible to still feed everybody after a complete collapse of the agricultural system?'" he says. "All solutions until this book focused on food storage, the survivalist method of putting cans in closets. But for global catastrophes, you'd need at least five years of supplies -- think bedroom size, not just a closet."
That big a stockpile just isn't possible globally, let alone in America, says Pearce. Families simply don't have enough money, and stockpiling would only raise food prices, causing more of the world's poor to starve.
Worry not, says Pearce. Even if the sun were blacked out for years at a time, killing all plants, we're still okay sans brimming bunkers of canned goods.
After looking at five crop-destroying catastrophes (sudden climate change, super-weeds, super-bacteria, super-pests and super-pathogens) and three sunlight-extinguishing events (super-volcano eruption, asteroid or comet impact, and nuclear winter), Pearce says we have a way to feed everyone on Earth for five years. That's enough time for the planet to recover, allowing a gradual return to the agricultural system we use today.
"We looked purely at technical viability -- ignoring all the social issues that currently cause millions to go hungry and die every year," he says.
Swap the Big Mac for Bugs and Slime
So how do we feed billions of hungry mouths if there is no more sunshine or farming? Swap your Big Mac and fries for bacterial slime and a side of bugs, and you'll be okay.
"We came up with two primary classes of solutions," Pearce says. "We can convert existing fossil fuels to food by growing bacteria on top of it -- then either eat the bacterial slime or feed it to rats and bugs and then eat them." The second (and easier) set of solutions uses partial rotting of woody plant fiber to either grow mushrooms or feed to insects, rats, cows, deer or chickens. "The trees are all dying from the lack of light anyway. If we use dead trees as an input, we can feed beetles or rats and then feed them to something else higher on the food chain," Pearce says. "Or just eat the bugs."
Of course, it would take some time to get such a new system established. In the interim, we could survive on fungi (mushrooms), bacteria and leaves. Tea steeped with pines from your front yard would provide a surprising amount of nutrition.
It wouldn't be a life devoid of little luxuries either, he says. "We could extract sugar from the bacterial slime and carbonate it for soda pop. We'd still have food scientists, too, who could make almost anything taste like bacon or tofurkey. It wouldn't be so bad."
Nuclear Winter and Climate Change
Pearce is confident we have the technical know how to get ourselves through almost any predictable catastrophe. Perhaps his most reassuring conclusion, though, is that the two most likely global catastrophes (nuclear winter and abrupt climate change) are the ones we have the most control over.
"We don't have to blow ourselves to smithereens if we don't want to," he jokes.
Pearce hopes his new book will help prevent the worst cases from actually happening and provide solutions to help people survive lesser catastrophes.
"The end of the book poses questions that we need to look at quickly," says Pearce. "We can feed everyone if we cooperate and do a little thinking ahead of time -- not in the dark when everyone is screaming. Life could continue to go on normally. Just a little dimmer."
Feeding Everyone No Matter What: Managing Food Security After Global Catastrophe is coauthored by Pearce and David Denkenberger, research associate at the Global Catastrophic Risk Institute. More information on the book can be found at: http://store.elsevier.com/Feeding-Everyone-No-Matter-What/Joshua-Pearce/isbn-9780128021507/

Story Source:
The above story is based on materials provided by Michigan Technological University. The original article was written by Danny Messinger. Note: Materials may be edited for content and length.
 
 
A specialized subset of lung cells can shake flu infection, yet they remain stamped with an inflammatory gene signature that wreaks havoc in the lung, according to a study published in The Journal of Experimental Medicine








Seasonal flu is caused by influenza virus, which can infect a variety of cell types in the lung. Infected cells are typically destroyed by the virus itself or by immune cells that attack infected cells. The resulting inflammation can linger on long after the virus has been eliminated leading to persistent symptoms and, in some cases, severe tissue damage.
Club cells are specialized cells that normally protect against inhaled microbes and pollutants. However, researchers from the Icahn School of Medicine at Mount Sinai in New York show that club cells are bad guys during flu infection. Although they are able to rid themselves of the flu virus, club cells fail to switch off expression of inflammatory genes causing prolonged pathology in the lungs even after the virus has been contained. Depletion of surviving club cells lessened destructive lung damage in flu-infected mice.
The authors confirm that human club cells show a similar inflammatory response to flu infection, so targeting club cells might be a strategy to shorten the duration of flu symptoms in humans.


Story Source:
The above story is based on materials provided by The Rockefeller University Press. Note: Materials may be edited for content and length.


Journal Reference:
  1. Nicholas S. Heaton, Ryan A. Langlois, David Sachs, Jean K. Lim, Peter Palese, and Benjamin R. Tenoever. Long-term survival of influenza virus infected club cells drives immunopathology. The Journal of Experimental Medicine, August 2014 DOI: 10.1084/jem.20140488
Scientists looking to understand -- and potentially thwart -- the influenza virus now have a much more encompassing view, thanks to the first complete structure of one of the flu virus' key machines. The structure, obtained by scientists at EMBL Grenoble, allows researchers to finally understand how the machine works as a whole, and could prove instrumental in designing new drugs to treat serious flu infections and combat flu pandemics.

If you planned to sabotage a factory, a recon trip through the premises would probably be much more useful than just peeping in at the windows. Scientists looking to understand -- and potentially thwart -- the influenza virus have now gone from a similar window-based view to the full factory tour, thanks to the first complete structure of one of the flu virus' key machines. The structure, obtained by scientists at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, allows researchers to finally understand how the machine works as a whole. Published in two papers in Nature, the work could prove instrumental in designing new drugs to treat serious flu infections and combat flu pandemics.




The machine in question, the influenza virus polymerase, carries out two vital tasks for the virus. It makes copies of the virus' genetic material -- the viral RNA -- to package into new viruses that can infect other cells; and it reads out the instructions in that genetic material to make viral messenger RNA, which directs the infected cell to produce the proteins the virus needs. Scientists -- including Cusack and collaborators -- had been able to determine the structure of several parts of the polymerase in the past. But how those parts came together to function as a whole, and how viral RNA being fed in to the polymerase could be treated in two different ways remained a mystery.
"The flu polymerase was discovered 40 years ago, so there are hundreds of papers out there trying to fathom how it works. But only now that we have the complete structure can we really begin to understand it," says Stephen Cusack, head of EMBL Grenoble, who led the work.
Using X-ray crystallography, performed at the European Synchrotron Radiation Facility (ESRF) in Grenoble, Cusack and colleagues were able to determine the atomic structure of the whole polymerase from two strains of influenza: influenza B, one of the strains that cause seasonal flu in humans, but which evolves slowly and therefore isn't considered a pandemic threat; and the strain of influenza A -- the fast-evolving strain that affects humans, birds and other animals and can cause pandemics -- that infects bats.
"The high-intensity X-ray beamlines at the ESRF, equipped with state-of-the-art Dectris detectors, were crucial for getting high quality crystallographic data from the weakly diffracting and radiation sensitive crystals of the large polymerase complex," says Cusack. "We couldn't have got the data at such a good resolution without them."
The structures reveal how the polymerase specifically recognises and binds to the viral RNA, rather than just any available RNA, and how that binding activates the machine. They also show that the three component proteins that make up the polymerase are very intertwined, which explains why it has been very difficult to piece together how this machine works based on structures of individual parts.
Although the structures of both viruses' polymerases were very similar, the scientists found one key difference, which showed that one part of the machine can swivel around to a large degree. That ability to swivel explains exactly how the polymerase uses host cell RNA to kick-start the production of viral proteins. The swivelling component takes the necessary piece of host cell RNA and directs it into a slot leading to the machine's heart, where it triggers the production of viral messenger RNA.
Now that they know exactly where each atom fits in this key viral machine, researchers aiming to design drugs to stop influenza in its tracks have a much wider range of potential targets at their disposal -- like would-be saboteurs who gain access to the whole production plant instead of just sneaking looks through the windows. And because this is such a fundamental piece of the viral machinery, not only are the versions in the different influenza strains very similar to each other, but they also hold many similarities to their counterparts in related viruses such as lassa, hanta, rabies or ebola.
The EMBL scientists aim to explore the new insights this structure provides for drug design, as well as continuing to try to determine the structure of the human version of influenza A, because although the bat version is close enough that it already provides remarkable insights, ultimately fine-tuning drugs for treating people would benefit from/require knowledge of the version of the virus that infects humans. And, since this viral machine has to be flexible and change shape to carry out its different tasks, Cusack and colleagues also want to get further snapshots of the polymerase in different states.
"This doesn't mean we now have all the answers," says Cusack, "In fact, we have as many new questions as answers, but at least now we have a solid basis on which to probe further."

Story Source:
The above story is based on materials provided by European Molecular Biology Laboratory (EMBL). Note: Materials may be edited for content and length.

Journal References:
  1. Alexander Pflug, Delphine Guilligay, Stefan Reich, Stephen Cusack. Structure of influenza A polymerase bound to the viral RNA promoter. Nature, 2014; DOI: 10.1038/nature14008
  2. Stefan Reich, Delphine Guilligay, Alexander Pflug, Hélène Malet, Imre Berger, Thibaut Crépin, Darren Hart, Thomas Lunardi, Max Nanao, Rob W. H. Ruigrok, Stephen Cusack. Structural insight into cap-snatching and RNA synthesis by influenza polymerase. Nature, 2014; DOI: 10.1038/nature14009
People with an algae virus in their throats had more difficulty completing a mental exercise than healthy people, and more research is needed to understand why, US scientists say.
 
A study in the Proceedings of the National Academy of Sciences showed that the was present in about half of 92 human subjects studied, and those who had it performed worse on certain basic tasks.
The virus, known as Acanthocystis turfacea Chlorella virus 1, or ATCV-1, also appeared to limit the cognitive abilities of mice.
The mice had a harder time navigating a maze and noticing new objects in their surroundings after they were infected.
It remains unclear if the virus was truly driving the drop in mental functioning. Researchers have not yet shown the cause and effect between the virus and the intelligence results.
"At this point we do not think that this virus should be considered as a threat to individual or public health," said lead researcher Robert Yolken, a virologist at Johns Hopkins University in Baltimore, Maryland.
"We do think that there is a need for additional medical and scientific studies of the effects of infectious agents which are common in the environment on human health and cognition," Yolken told AFP.
The virus was found by accident while scientists were analyzing microbes in the throats of healthy humans for a different study.
Experts have been studying viruses similar to ATCV-1 for 35 years, said senior author James Van Etten of the University of Nebraska, an expert on algal viruses.
Van Etten joined the research four years ago when Johns Hopkins scientists found ATCV-1's DNA sequences in the brain tissue of people who had died with such as schizophrenia.
"This finding was certainly surprising to us," Van Etten told AFP.
"These viruses are ubiquitous in fresh water ponds and streams throughout the world," Van Etten said.
He noted that the virus—previously thought to only infect algae—could make its way into the human body when people swallow water while swimming.
There might also be another host in nature, such as mosquito larvae, he said.
But the nature of the disease is still in the early stages of analysis.
It is also unknown if the virus's effects on the brain are lasting or temporary.
Scientists have long understood that viruses interact with DNA, and further studies could shed more light on the role of the virus on cognition.
"As more studies like this are conducted, I believe we'll find out there's even more interaction between viruses, bacteria and fungi that are either ingested or breathed into our noses and mouths and the overall human condition," said Jordan Josephson, ear nose and throat specialist at Lenox Hill Hospital in New York, who was not involved in the study.
"I believe this new research is just the tip of the iceberg in linking viruses in the human oral cavity to the development of various health conditions."
More information: Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice, PNAS, Robert H. Yolken, 16106–16111, DOI: 10.1073/pnas.1418895111
Journal reference: Proceedings of the National Academy of Sciences
(HealthDay)—Until recently, insect-transmitted Chagas disease was found mainly in Latin America and South America, but it has made its way to the United States over the past few years.
The potentially fatal illness is typically transmitted via the bite of the "kissing bug," which feeds on the faces of humans at night. And now a new study suggests that common might be carriers as well.




"We've shown that the bedbug can acquire and transmit the parasite. Our next step is to determine whether they are, or will become an important player in the epidemiology of Chagas disease," study senior author Michael Levy, assistant professor in the department of Biostatistics and Epidemiology, University of Pennsylvania's Perelman School of Medicine, said in a university news release.
According to background information from the researchers, Chagas disease affects 6 million to 8 million people worldwide and kills about 50,000 a year, and is one of the most common and dangerous illnesses in Latin America. The disease, caused by the microscope parasite Trypanosoma cruzi, can progress without symptoms for years, but can end up attacking the heart and causing heart failure, the researchers explained.
Recently, "we are finding new evidence that locally acquired human transmission is occurring in Texas," Melissa Nolan Garcia, a research associate at Baylor College of Medicine in Houston told HealthDay earlier this month. Her team reported the findings at the annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans.
It's been long known that "kissing bugs" can transmit Chagas disease to people through their feces, but bedbugs were thought to be disease-free.
However, in a series of experiments, Levy's team found that the parasite that causes Chagas disease can be passed back and forth between mice and bedbugs.
"There are some reasons to worry—bedbugs have more frequent contact with people than kissing bugs, and there are more of them in infested houses, giving them ample opportunity to transmit the parasite. But perhaps there is something important we don't yet understand about them that mitigates the threat," Levy added.
The parasite that causes Chagas disease appears especially at home in the guts of bedbugs, added study co-author Renzo Salazar, a biologist at the Universidad Peruana Cayetano Heredia in Lima, Peru.
"I've never seen so many in an insect. I expected a scenario with very low infection, but we found many parasites—they really replicate well in the gut of the bedbugs," Salazar said in the news release.
The number of people infected with the parasite that causes Chagas disease is growing in the United States and now numbers about 300,000, according to the U.S. Centers for Disease Control and Prevention.
"The we have here don't come into homes frequently like the more dangerous species in South and Central America do," Levy noted. However, "I am much more concerned about the role of bedbugs," he said. "They are already here—in our homes, in our beds and in high numbers. What we found has thrown a wrench in the way I think about transmission, and where Chagas disease could emerge next."
The findings appear online Nov. 17 in the American Journal of Tropical Medicine and Hygiene.
More information: The U.S. Centers for Disease Control and Prevention has more about Chagas disease.
Journal reference: American Journal of Tropical Medicine and Hygiene search and more info

BALTIMORE, MARYLAND—Medical engineers have long used nano-sized fibers as sturdy scaffolds for growing tissues. Now, researchers are developing nanofiber meshes that might suck bugs out of wounds and accelerate healing, they report here this week at the 61st annual AVS meeting. Scientists have injected cell-carrying nanofibers into wounds to jump-start tissue repair, but to design a truly smart dressing, they need to know how the material interacts with bacteria. After testing nanofibers of various sizes, researchers found that bugs transfer most easily to nanofibers with diameters that match the bacteria’s sizes. When the scientists placed nanofibers in a petri dish of Staphylococcus aureus, a bacterium involved in chronic infection, the bugs quickly attached themselves to 500-nanometer-wide fibers (as seen above), but hardly onto fibers with larger diameters. When the researchers coated the nanofibers with different compounds and tested them on the bacteria Escherichia coli, also responsible for chronic wounds, the bugs formed bridges on fibers coated with allylamine, a colorless organic compound, but stayed away from fibers coated with acrylic acid. The researchers, who plan to test the meshes on composites that resemble human skin, hope that they will eventually lead to smart wound dressings that could prevent infections. Doctors could stick the nano–Band-Aid on a wound and simply peel it off to get rid of the germs.

Posted in Health, Technology

 

Viruses pull a lot of dirty tricks to dodge our immune defenses and make us sick, but now scientists have come up with a trick of their own. Researchers have discovered that prompting cells to combat bacteria can also help them fight off viruses, even though the cells presumably wouldn’t have the right weapons to do so. “This would be analogous to, in a football game, arming the defense with baseball bats,” says Andrew Gewirtz, a mucosal immunologist at Georgia State University in Atlanta. The finding could solve a vaccine mystery, as well as lead to new ways to combat infectious diseases.



Your cells don’t respond the same way to bacteria and viruses. They switch on different genes and release different mixtures of chemical messengers and protective molecules. That’s why Gewirtz and his colleagues were taken aback by the results of an experiment they performed 6 years ago. The researchers were testing whether an injection of flagellin, a protein that’s part of the tails (or flagella) some bacteria use to propel themselves, activates the body’s antibacterial defenses. Their findings showed that it did, enabling mice to subsequently survive what should have been a lethal dose of harmful intestinal bacteria.
The surprise came when Gewirtz’s team infected the mice with rotavirus, a common cause of severe diarrhea in young children. Even though the virus doesn’t have a flagellum, injecting the rodents with flagellin in advance protected them against the pathogen.
In their new study, published online today in Science, Gewirtz and his colleagues figured out why. The researchers determined which two pathogen-sensing molecules enable cells to recognize the injected flagellin. When the cells detect flagellin, they spur other cells to emit interleukin-22 (IL-22) and interleukin-18 (IL-18), molecular signals that help orchestrate a defensive response. That presumably would help kill off bacterial invaders, but why does it work against viruses?
The answer may lie in the habits of the rotavirus, which invades cells lining the small intestine. IL-22 makes intestinal cells more resistant to viral invasion, whereas IL-18 thwarts the virus by spurring cells it has already infected to commit suicide. So when these molecules are activated, they fight bacteria as well as rotavirus. Indeed, injecting mice with IL-22 and IL-18 triggered the same antiviral effect as flagellin, the team found.
Gewirtz says that this mechanism might work because “it’s not what the virus is used to.” Rotavirus evolved to evade the body’s antiviral defenses, but it can’t counteract the response activated by flagellin or the combination of IL-22 and IL-18.  
“It’s a very nicely documented story,” says Roger Glass, a rotavirologist at the National Institutes of Health in Bethesda, Maryland. “They work through all possible explanations.” The crossover protection the authors observed is unexpected because the opposite often occurs, says immunologist and physician Robert Sabat of Charité University Medicine Berlin. For example, viral lung infections often leave patients more vulnerable to bacterial infections, not less.
Glass adds that the results might solve a mystery about the two new oral rotavirus vaccines introduced within the last decade. The vaccines contain weakened forms of the virus and are much more effective in developed countries than in developing countries, where rotavirus kills more than 400,000 children every year. Children in developing countries have probably been exposed to more flagella-carrying bacteria when they are vaccinated, he says. As a result, their cells might destroy the rotaviruses in the vaccine before they can develop immunity.
Researchers don’t expect the discovery to have much impact on global mortality from rotavirus infections. Treating children with IL-22 and IL-18 wouldn’t be feasible in developing countries where the virus is a major killer because of their limited medical facilities, Glass says. In developed countries, though, the combination might benefit children and adults whose immune systems are impaired because of cancer treatment or diseases like AIDS and who are vulnerable to rotavirus infections.
Sabat notes that researchers have already completed some clinical trials of IL-22 and IL-18 in cancer patients, and IL-18 did cause side effects such as fever, nausea, and difficulty breathing. However, he says, “a combination of IL-22 and low-dose IL-18 might be well tolerated.”
IL-22 and IL-18 might have other uses as well. “We think the system we’ve developed will be broadly applicable to other viral infections,” Gewirtz says. He and his colleagues are now testing whether the combination allows mice to resist a range of viruses, including norovirus, a gastrointestinal pathogen notorious for causing outbreaks on cruise ships.
Posted in Biology, Health

Abstract

Background

Acute respiratory infections (ARIs) are by far the most common reason for prescribing an antibiotic in primary care, even though the majority of ARIs are of viral or non-severe bacterial aetiology. Unnecessary antibiotic use will, in many cases, not be beneficial to the patients' recovery and expose them to potential side effects. Furthermore, as a causal link exists between antibiotic use and antibiotic resistance, reducing unnecessary antibiotic use is a key factor in controlling this important problem. Antibiotic resistance puts increasing burdens on healthcare services and renders patients at risk of future ineffective treatments, in turn increasing morbidity and mortality from infectious diseases. One strategy aiming to reduce antibiotic use in primary care is the guidance of antibiotic treatment by use of a point-of-care biomarker. A point-of-care biomarker of infection forms part of the acute phase response to acute tissue injury regardless of the aetiology (infection, trauma and inflammation) and may in the correct clinical context be used as a surrogate marker of infection, possibly assisting the doctor in the clinical management of ARIs.




Objectives

To assess the benefits and harms of point-of-care biomarker tests of infection to guide antibiotic treatment in patients presenting with symptoms of acute respiratory infections in primary care settings regardless of age.

Search methods

We searched CENTRAL (2013, Issue 12), MEDLINE (1946 to January 2014), EMBASE (2010 to January 2014), CINAHL (1981 to January 2014), Web of Science (1955 to January 2014) and LILACS (1982 to January 2014).

Selection criteria

We included randomised controlled trials (RCTs) in primary care patients with ARIs that compared use of point-of-care biomarkers with standard of care. We included trials that randomised individual patients as well as trials that randomised clusters of patients (cluster-RCTs).

Data collection and analysis

Two review authors independently extracted data on the following outcomes: i) impact on antibiotic use; ii) duration of and recovery from infection; iii) complications including the number of re-consultations, hospitalisations and mortality; iv) patient satisfaction. We assessed the risk of bias of all included trials and applied GRADE. We used random-effects meta-analyses when feasible. We further analysed results with a high level of heterogeneity in pre-specified subgroups of individually and cluster-RCTs.

Main results

The only point-of-care biomarker of infection currently available to primary care identified in this review was C-reactive protein. We included six trials (3284 participants; 139 children) that evaluated a C-reactive protein point-of-care test. The available information was from trials with a low to moderate risk of bias that address the main objectives of this review.
Overall a reduction in the use of antibiotic treatments was found in the C-reactive protein group (631/1685) versus standard of care (785/1599). However, the high level of heterogeneity and the statistically significant test for subgroup differences between the three RCTs and three cluster-RCTs suggest that the results of the meta-analysis on antibiotic use should be interpreted with caution and the pooled effect estimate (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92; I2 statistic = 68%) may not be meaningful. The observed heterogeneity disappeared in our preplanned subgroup analysis based on study design: RR 0.90, 95% CI 0.80 to 1.02; I2 statistic = 5% for RCTs and RR 0.68, 95% CI 0.61 to 0.75; I2 statistic = 0% for cluster-RCTs, suggesting that this was the cause of the observed heterogeneity.
There was no difference between using a C-reactive protein point-of-care test and standard care in clinical recovery (defined as at least substantial improvement at day 7 and 28 or need for re-consultations day 28). However, we noted an increase in hospitalisations in the C-reactive protein group in one study, but this was based on few events and may be a chance finding. No deaths were reported in any of the included studies.
We classified the quality of the evidence as moderate according to GRADE due to imprecision of the main effect estimate.

Authors' conclusions

A point-of-care biomarker (e.g. C-reactive protein) to guide antibiotic treatment of ARIs in primary care can reduce antibiotic use, although the degree of reduction remains uncertain. Used as an adjunct to a doctor's clinical examination this reduction in antibiotic use did not affect patient-reported outcomes, including recovery from and duration of illness. However, a possible increase in hospitalisations is of concern. A more precise effect estimate is needed to assess the costs of the intervention and compare the use of a point-of-care biomarker to other antibiotic-saving strategies.
 

Plain language summary

Use of rapid point-of-care testing for infection to guide doctors prescribing antibiotics for acute respiratory infections in primary care settings

Review question
We reviewed the evidence of the effect and safety of a rapid test of infection at point-of-care for using antibiotics in people with acute respiratory infections (ARIs) (e.g. common colds) in primary care.

Background
Antibiotic treatment is common in ARIs despite the fact that the vast majority are caused by viruses, against which antibiotics are ineffective and unnecessary. The concern is that antibiotics may cause side effects and are directly associated with antibiotic resistance in common bacteria, causing treatment failure and complications, including death. Antibiotics have a modest, if any, effect against the majority of ARIs. Their use must be balanced against risking higher levels of antibiotic resistance, side effects and costs. Biomarkers of infection are proteins or components of the immune system that participate in the body's acute response to infection. No tests are currently able to provide perfect diagnostic accuracy for infections. This could lead to over- as well as under-diagnosis. Some tests have been developed that assess the presence of infections by looking for certain of these biomarkers. These are rapid tests that may be used during the consultation by primary care doctors when people go to see them with symptoms of an ARI. In the correct clinical context these point-of-care tests could assist primary care doctors by identifying people with infections that are most likely to respond to antibiotics. We looked at the evidence for these tests to assess the possible harms and benefits of implementing such a strategy in primary health care.

Study characteristics
We included six studies with a total of 3284 participants with ARIs from primary care settings (point-of care test: C-reactive protein). Two of the included studies received direct financial support from manufacturers. The evidence is current to January 2014.

Key results
The only point-of-care biomarker of infection currently available to primary care identified in the review was C-reactive protein. A reduction in antibiotic use is likely to be achieved by a C-reactive protein point-of-care test but due to differences in the designs of the included studies, it was not possible to obtain a precise effect estimate of the reduction. There were no deaths in the studies and we did not find evidence suggesting that time to recovery from ARIs and their duration were longer, nor that levels of patient satisfaction or number of re-consultations were affected in the C-reactive protein group. However, a possible increase in the risk of hospital admission cannot be ruled out.

Quality of the evidence
We ranked the evidence as of moderate quality according to the GRADE levels due to an imprecise effect estimation.

Conclusion
Used as an adjunct to a doctor's clinical examination point-of-care tests (e.g. C-reactive protein) can reduce antibiotic use in ARIs in general practice. The possibility of an increased risk of hospital admission suggests that care must be taken in how these tests are used. A more precise effect estimate is needed to assess the costs of the intervention and compare the use of a point-of-care biomarker to other antibiotic-saving strategies.

 

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