Virology

Researchers describe new viral mechanism for balancing alternate host species

Anonymous — Thu, 19 Apr 2018 15:48:53 +0000

Researchers describe new viral mechanism for balancing alternate host species Anonymous (not verified) Thu, 04/19/2018 - 09:48

BioFrontiers

Sawyer Lab, BioFrontiers Institute, �鶹ӰԺ

�鶹ӰԺ researchers studying virus spillover have uncovered a clue explaining why dengue viruses reach high concentrations in humans, but not in primates, their presumed natural source. The work was performed by the lab of Dr. Sara Sawyer at the BioFrontiers Institute, and published recently in the journal eLIFE.

Dengue viruses cause disease in approximately 100 million individuals each year. As of yet, no vaccine exists to protect against all human dengue viruses. Dengue is related to yellow fever virus, Zika virus, and West Nile virus, all of which spread via mosquitoes in highly populated areas. Human dengue viruses emerged from primates, yet dengue does not reach high titers in primate populations.

“This paper characterizes one way dengue virus avoids detection by the human immune system. Despite being genetically very similar, small changes that exist between humans and their primate relatives affect the ability of dengue virus to replicate,” said Alex Stabell, a graduate student in Dr. Sara Sawyer’s lab and lead author of the study.

The research shows dengue virus cleaves human STING protein, impairing the body’s immune response. In other primates, dengue does not cleave STING, lessening the pathogenicity of the disease. The authors trace this disparity to residues 78 and 79 in the STING protein, which read ‘RG’ in humans. Monkeys and other mammals have different residues in these locations, causing STING to evade detection by viral proteases. Conversion of these residues to the human-encoded ‘RG’ renders all primate STINGs susceptible to viral cleavage.

“Dengue viruses have evolved to suppress innate immunity in humans in order to increase viral titers and spread,” the authors note. “What we have uncovered is a brilliant method for balancing alternate host species.”

In dense human populations, the cost of severe disease is outweighed by excellent spread. But in smaller animal populations, decreased disease impact allows the virus to use these animals as a long-term reservoir. Thus, dengue viruses have evolved to achieve ideal pathogenesis in both humans and nonhuman primates.

“Hopefully, the species-specific differences we discovered in this paper will help guide further studies, and help us better understand dengue virus replication,” said Stabell. These results will help researchers identify better laboratory animals for studying dengue virus pathogenesis, a crucial step in the development of drugs and vaccines.

Co-authors of the study include Rebekah Gulberg and Rushika Perera of Colorado State University.

The research was supported by the National Institutes of Health, the National Science Foundation, and the Burroughs Wellcome fund.

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Sara Sawyer Receives Richard M. Elliott Memorial Award in Glasgow, Scotland

Anonymous — Tue, 23 Jan 2018 07:00:00 +0000

Sara Sawyer Receives Richard M. Elliott Memorial Award in Glasgow, Scotland Anonymous (not verified) Tue, 01/23/2018 - 00:00

BioFrontiers Institute

For billions of years, the battle between cells and viruses has been a primary driver of evolution. �鶹ӰԺ researcher Dr. Sara Sawyer has dedicated her career to this relationship, combining methods from virology and molecular evolution to investigate emerging human and animal viruses. Sawyer, an Associate Professor in the Department of Molecular, Cellular, and Developmental Biology and core faculty member of the BioFrontiers Institute, is receiving the Richd M. Elliott Memorial Award from the University of Glasgow Centre for Virus Research. This award is in honor of Richard M. Elliott, the former Chair of Infectious Diseases at the University of Glasgow, and a pioneer in the field of emerging viruses.

Richard M. Elliott was a pioneer in the field of bunyaviruses, which are RNA viruses transmitted by arthropod carriers such as mosquitoes. His work was pivotal in understanding the structure and function of viral genomes.

“I came to virology through the backdoor, entering this field originally so that I could test ideas in evolutionary theory,” Sawyer commented. “I am really honored to receive this recognition by the virology community.”

Sawyer frequently turns to genomics to trace the evolutionary history of antiviral genes in humans and primates, as well as viral proteins that can evade the immune system. Using tools from molecular evolution, Sawyer sheds light on why humans are resistant to animal viruses and how viruses evolve the ability to infect new species. Her work in virology will be recognized at the 23rd Glasgow Virology Workshop on February 10th.

“The prize really belongs to my whole lab, past and present,” Sawyer said. “Many people have worked together to mold the new field we are helping to pioneer, which is to combine evolutionary theory and experimentation to understand how viruses jump from animals to humans.”

Sawyer is implementing innovative approaches to continue the work of pioneering virologists such as Richard M. Elliott. Her achievements have already been recognized by the Omenn Prize for the best Evolutionary Medicine paper of 2013, and a Presidential Early Career Award for Scientists and Engineers, given to her in 2011 by President Barack Obama in a ceremony held at the White House. By merging disciplines, Sara Sawyer is beginning to answer longstanding questions about how new viral diseases emerge from nature.

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New broad-spectrum antiviral protein can inhibit HIV, other pathogens in some primates

Anonymous — Wed, 18 Jan 2017 22:31:27 +0000

New broad-spectrum antiviral protein can inhibit HIV, other pathogens in some primates Anonymous (not verified) Wed, 01/18/2017 - 15:31

CUBT - CU �鶹ӰԺ Today

�鶹ӰԺ researchers have discovered that a protein-coding gene called Schlafen11 (SLFN11) may induce a broad-spectrum cellular response against infection by viruses including HIV-1.

The new research, which was recently published in the journal PLOS Pathogens, found that SLFN11's antiviral potency is highest in non-human primate species such as chimpanzees and orangutans, but less effective in humans and gorillas, indicating that the gene's effects have become highly species-specific over time when it comes to fighting off HIV-1.

"The findings suggest that HIV-1 has been able to take advantage of this relaxed selection in humans," said Alex Stabell, a graduate researcher in CU �鶹ӰԺ's BioFrontiers Institute and lead author of the new research.

The human immune system contains various protein-encoding genes that are able to recognize the foreign signatures of RNA viruses and prevent their replication, providing a genetic line of defense against animal-based (zoonotic) diseases. HIV-1 is one of several zoonotic retroviruses that has been able to subvert these defenses and adapt to human hosts via mechanisms that are still being studied. HIV-1 was passed to humans from primates.

In 2012, researchers demonstrated that the SLFN11 gene is capable of limiting HIV-1 replication early in the virus's lifecycle, but the mere presence of SLFN11 in humans has not, to date, provided an effective bulwark against the disease.

"The immune system contains some of the most rapidly evolving genes in mammalian genomes, and what we are finding is that the immune systems of even very closely-related species, such as humans and chimpanzees, differ in dramatic ways," said Sara Sawyer, an associate professor in the BioFrontiers Institute and senior author of the new study.

To investigate why, the CU �鶹ӰԺ researchers analyzed data from primate genome projects around the country to get a broader picture of the gene's evolutionary history and compare its antiviral effects in other primate species.

"We examined different versions of this gene in other primate species, looking for positive selection over time," said Stabell. "Genes tend to want to be conserved, to stay the same. But a rapidly adapting retrovirus can force their hand."

The analysis found that over millions of years, the antiviral effectiveness of the gene diverged by species to the point where the SLFN11 proteins encoded by chimpanzees, orangutans, gibbons and marmosets now inhibit HIV-1 replication far more effectively than those produced by human, gorillas and bonobos.

The researchers also found that SLFN11 can have antiviral effects beyond just HIV-1. Even when HIV-1 is absent from a host's system, the gene broadly restricts protein production based on non-optimized codons, essentially reprogramming cells to create a general antiviral state.

The findings could provide new avenues of inquiry for future pharmaceutical and gene therapy research centered on HIV-1.

Originally published by CU �鶹ӰԺ Today

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$1.1 million grant funds CU �鶹ӰԺ research into next-generation vaccines

Anonymous — Fri, 04 Nov 2016 06:00:00 +0000

$1.1 million grant funds CU �鶹ӰԺ research into next-generation vaccines Anonymous (not verified) Fri, 11/04/2016 - 00:00

BioFrontiers

The �鶹ӰԺ has received a $1.1 million grant from the Bill & Melinda Gates Foundation to develop next-generation vaccines that require no refrigeration and defend against infectious diseases with just one shot.

If successful, those advancements could radically transform the difficult task of dispensing life-saving immunizations in developing countries — and improve convenience in every part of the world.

Professor Bob Garcea of the Department of Molecular, Cellular and Developmental Biology and the BioFrontiers Institute has teamed up with Professors Ted Randolph and Al Weimer of the Department of Chemical and Biological Engineering in a unique collaboration that applies a wide range of skillsets and ideas to the pressing challenge of delivering vaccines to patients in developing countries. All three investigators work in the Jennie Smoly Caruthers Biotechnology Building (JSCBB) at CU �鶹ӰԺ, but their research areas have very different emphases.

“It’s really merging three different people with three different sets of expertise into one project,” Garcea said.

In Garcea’s lab, located in the Jean and Jack Thompson Vaccine Research Laboratories of the JSCBB, investigators work on new vaccines such as those for human papillomavirus, a leading cause of cervical cancer that is particularly devastating to women in developing countries.

One corridor away, Randolph’s team, which focuses on creating stable dosage forms for therapeutic proteins and vaccines, developed a process for making vaccines thermostable, or resistant to damage from heat or cold. In this glassy powder state, the vaccine can be stored at temperatures as high as 120 degrees Fahrenheit for three to four months without losing efficacy, Randolph said.

The two began collaborating about two years ago and even formed a spinoff company, Vitravax Inc., which is seeing successful results in vaccine studies conducted in mice.

The Gates Foundation grant will take these innovations a step further by combining the thermostable vaccine powders with techniques developed in the Weimer lab that allow uniform nanoscopic protective layers of aluminum oxide to be applied to vaccine microparticles. This coating process, called atomic layer deposition, not only provides a nanometer-thick protective barrier for the vaccine particles but also helps trigger the body’s immune response.

The trio is now forming extended release, multilayer microparticulate vaccine dosage forms, composed of an inner core of stabilized vaccine coated with aluminum oxide layers and an outer layer of vaccine, all embedded in a glassy powder. When the formulation is injected, the outer layer provides an initial vaccine dose. Next, the aluminum oxide layer slowly dissolves, eventually releasing the inner core which acts as a second dose of vaccine. Patients receive their second or third “dose” without ever knowing it and without a return trip to the doctor.

Although each step of the process has worked independently, researchers cautioned that moving from small test batches in the lab to manufacturing millions of vaccines for public use is a challenging process that may not succeed quickly – or at all.

“We’ve done many of the individual parts of this project,” Randolph said. “Now we’ve got to put those pieces together, and have it work.”

Still, investigators say they’re optimistic about the collaboration, which might never have happened if not for their proximity on CU-�鶹ӰԺ’s East Campus and the interdisciplinary mission of the BioFrontiers Institute, which seeks to drive innovation by combining researchers from different fields.

“One of the hopes (of the BioFrontiers Institute) is that investigators will, by their proximity, do new and interesting things,” said Garcea, who is a member of the Institute. “In a sense, we’ve fulfilled the mission. If the technology works, we’ve really fulfilled the mission.”

The Randolph and Weimer Labs are part of the Department of Chemical and Biological Engineering. The Garcea lab is part of the Department of Molecular, Cellular and Developmental Biology at CU �鶹ӰԺ and the BioFrontiers Institute. At the University of Colorado BioFrontiers Institute, researchers from the life sciences, physical sciences, computer science and engineering are working together to uncover new knowledge at the frontiers of science and partnering with industry to make their discoveries relevant.

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Yeast gene rapidly evolves to attack viruses

Anonymous — Thu, 06 Oct 2016 06:00:00 +0000

Yeast gene rapidly evolves to attack viruses Anonymous (not verified) Thu, 10/06/2016 - 00:00

BioFrontiers

Humans have used Saccharomyces cerevisiae yeast in baking, brewing and winemaking for millennia. New research from the University of Idaho and the �鶹ӰԺ reveals another way that yeast species can help our species: by demonstrating how viruses interact with their hosts, and how hosts may evolve to fight back.

Paul Rowley, an assistant professor of biological sciences in the UI College of Science, and Sara Sawyer, an associate professor of molecular, cellular and development biology in the �鶹ӰԺ's BioFrontiers Institute, have discovered that a gene in S. cerevisiae and multiple other Saccharomyces yeast species appears to rapidly evolve to recognize and destroy attacking viruses.

The finding is surprising because the gene, called XRN1, is not associated with immunity. Rather, it builds a "housekeeping" protein that helps the cell clean out old molecules, according to the researchers.

"Evolution can actually shape these essential proteins and redirect them to interfere with virus replication," Rowley said. "It is interesting to think that non-immunity proteins are having a role to play in viral defense. Going forward it is going to be fascinating to see how many other essential proteins are moonlighting as antiviral factors."

Almost all species of yeast involved in food- and drink-making, and many other yeasts are chronically infected with viruses. These viruses hold their genetic information in RNA, which is also an important genetic molecule in yeast and all other organisms.

"Viruses are typically quite specific in the hosts that they infect. New diseases like Zika arise when a virus from one species evolves the ability to infect another," Sawyer said.

"We have demonstrated an approach for finding the host genes that keep viruses in their place, making it hard for them to infect new species. With this study, the approach has now been demonstrated to work from yeast to humans," she said.

XRN1 makes a protein that functions like a garbage disposal in yeast cells, breaking down the cell's old RNA. But by genetically altering the yeast cells, scientists have shown the XRN1 protein also can break down viral RNA.

"People saw that if you remove XRN1, the virus replicates at very high levels within the cell," Rowley said. "If we express XRN1 at a high levels, it will knock the virus out completely. We can cure the yeast of the virus."

Scientists' prevailing wisdom said the XRN1 protein wasn't specifically targeting viral RNA -- just grabbing it by coincidence, as if it were yeast RNA in need of disposal. However, Rowley and Sawyer's new research, published in the journal PLoS Pathogens, demonstrates that XRN1 is evolving specifically to combat viruses.

Rowley used genetic analysis tools to examine XRN1 in all known species of Saccharomyces yeast and found it is changing rapidly, much quicker than expected by chance. To test whether it is actually responding to the virus, Rowley and Sawyer removed the gene and swapped in XRN1 from other Saccharomyces yeast species.

"When we put in XRN1 from a different species, all of a sudden the virus started to grow rapidly. It's as if we completely deleted XRN1," Rowley said. "Challenging XRN1 from different species against a virus they've never encountered, it's like they're blind to it."

XRN1's housekeeping functions, on the other hand, worked just fine -- indicating that XRN1 evolves differently in each Saccharomyces species in order to target the specific viruses infecting them, while still maintaining the essential role as a cellular garbage disposal.

Beyond providing a model for understanding the "genetic arms race" of host-virus interaction, Rowley said, he and Sawyer's findings also have applications to human health.

XRN1 is an evolutionarily ancient gene, found in species from yeasts to humans. It serves the same RNA-disposal function in humans, and it also can break down viral RNA. In fact, some human viruses target XRN1: Polio degrades it, and the virus that causes Hepatitis C blocks it from attacking its RNA.

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Using evolution to fight disease

Anonymous — Thu, 25 Jun 2015 06:00:00 +0000

Using evolution to fight disease Anonymous (not verified) Thu, 06/25/2015 - 00:00

BioFrontiers

New BioFrontiers lab uses evolution to fight disease

by Paul McDivitt

Photo: Sara Sawyer

Ebola comes from bats, HIV from primates, and new strains of influenza from birds and pigs. With zoonotic diseases – those capable of transmission from animals to humans – grabbing headlines across the globe, understanding how they work has never been more important.

That’s the mission of a new team of researchers led by Dr. Sara Sawyer at the BioFrontiers Institute. By analyzing the genomes of hosts and viruses alike, Sawyer and her team hope to shed some light on why humans are resistant to most animal viruses, and how animal viruses evolve the ability to overcome these obstacles and infect humans.

“These are exactly the kinds of targets that we’re after – mammalian genes that determine why viruses infect the species that they do and why they don’t infect the species that they don’t,” said Sawyer.

One example of the work that Sawyer’s lab does is a project studying how HIV – the virus that causes AIDS – jumped from primates to humans, and why the virus affects humans differently than some primates.

“Chimpanzees and humans only differ in their genetic code by two percent, yet HIV doesn’t make chimpanzees nearly as sick as it makes humans,” said Sawyer. “So somewhere in that two percent difference in their genetic code may lie the answer to surviving this devastating disease.”

Sawyer’s team, which moved to Colorado from the University of Texas at Austin, works primarily with HIV, dengue (the virus that causes dengue fever) and influenza.

They utilize samples from a variety of primate, rodent, bat and other mammalian species in order to understand the genetic reasons why some species are susceptible and others aren’t. Genetics may provide the answer to how viruses evolve to infect new species. One of the specialties of this lab is bringing wildlife samples into the lab rather than relying on materials from model organisms (the lab recently received part of a wolf heart in the mail).

The lab, which is housed in the Jennie Smoly Caruthers Biotechnology Building on the CU-�鶹ӰԺ east campus, operates at biosafety level two, which required a substantial retrofit before Sawyer’s team could move in. (The lab does not work with live strains of Ebola, which is highly regulated and requires a biosafety level four lab.)

Sawyer is carving out a niche in the field of virology thanks to her background in evolutionary biology. By applying techniques from evolutionary biology Sawyer hopes to better understand interactions between viruses and their hosts, which could lead to novel methods for preventing future outbreaks. For example, by predicting when and where viruses could transfer to humans, we could implement simple public health measures to protect people – an intriguing prospect given the rapid proliferation of deadly viruses such as Ebola.

“There just aren’t a lot of people doing molecular virology who are also interfacing with nature, and bringing animal samples from the wild into the lab. But, if you are trying to understand where humans are running into these viruses in the natural world, model organisms won’t help you with that,” said Sawyer. “Things can be done to protect people from these viruses, we just know so little about what’s dangerous.”

Sawyer utilizes an evolutionary model called the “host-virus arms race” in her work. This model says that viruses experience constant selection to better infect and spread in their hosts. In turn, though, hosts evolve to perfect their immune arsenal against viruses. This tit-for-tat evolution leads to an arms race that is ever escalating, and drives rapid evolution in both the virus and the host genome.

But studying arms races requires lots of genetic sequencing data. “Like every other field, biology is experiencing a revolution where we’re getting instrumentation that can measure things in enormous numbers,” said Sawyer. “Big data has hit biology.”

Sawyer and her team were impressed by Tom Cech’s interdisciplinary vision for BioFrontiers, and think the institute will help their research as well as the career prospects of current and future members of the lab. She has been particularly impressed in the many bioinformatic training opportunities that are offered in the Jennie Smoly Caruthers Biotechnology Building, including the IQ Biology Interdisciplinary Quantitative Biology PhD certificate program.

“Most of the departments hiring new faculty right now are looking for people doing things like next-generation sequencing, systems biology, bioinformatics, and high-throughput biology,” said Sawyer. “The problem is that there aren’t very many trainees out there that meet that job description, yet that’s what many departments are seeking. I am impressed that Dr. Cech is addressing this problem head-on.”

She believes her team will benefit greatly from training opportunities provided by BioFrontiers, as well as collaboration with other BioFrontiers researchers. Dr. Nick Meyerson, a postdoc in Sawyer’s lab overseeing all of the lab’s projects, agrees.

“Being at an institute like this, where it’s so interdisciplinary, I think it will be very easy to develop new angles on projects and interface with professors that have ideas that we wouldn’t be exposed to anywhere else,” he said.

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Stopping cancer's knock on the door

Anonymous — Tue, 06 Dec 2011 07:00:00 +0000

Stopping cancer's knock on the door Anonymous (not verified) Tue, 12/06/2011 - 00:00

BioFrontiers

Stopping cancer's knock on the door

As a self-proclaimed “science nerd” in a Beijing high school, Hubert Yin considered biochemistry to be the ultimate in cool. It was the only science, he felt, that was capable of explaining what he thought was the most complex, most beautiful thing on earth– life at the molecular level.

This sense of awe led him to graduate at the top of his class at Peking University in applied chemistry, and then propelled him to the other side of the globe for a doctorate in organic and bioorganic chemistry from Yale, and post-doctoral work at the University of Pennsylvania School of Medicine. Now he is an assistant professor of chemistry and biochemistry, a University of Colorado Cancer Center Investigator, and a Biofrontiers Institute faculty member at the �鶹ӰԺ.

“I was totally amazed by this ‘in depth’ understanding of how life works,” says Yin. “I was attracted to the idea of rational design where we use all of these fun toys, like computer simulation and protein engineering, to design something novel and useful, like cancer drugs.”

Yin is searching for unconventional drug targets: the ones that have been overlooked by drug companies. His focus is on cell membrane proteins, which act as windows and doors to the inner workings of all cells. Some viruses knock on the doors of the cell, hijacking normal cell functions, allowing them to gain entry through the cell membrane and take over the cell. Scientists have yet to discover just how that “knock on the door” occurs.

Yin is studying this process with the Epstein-Barr virus (shown, left), also known as Human Herpesvirus-4 (HHV-4), which was identified in 1964 as a cancer-causing virus. It is one of the most common viruses in humans, affecting approximately 95 percent of the U.S. population by adulthood. It is also infamously known as the virus that causes mononucleosis.

HHV-4 is one of at least six viruses that are known to cause cancer, and it is associated with some of the rare cancers: Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma and other central nervous system lymphomas. Because it is so common and is associated with so many cancers, HHV-4 is an attractive target for the development of cancer vaccines and treatment.

Computer simulations have allowed Yin to study the process viruses use to knock on the doors of cells. He has rebuilt the Latent Membrane Protein, or LMP-1, down to the last atom using computer simulations in a membrane environment. LMP-1, when activated, induces an inflammatory response to HHV-4, which allows cancers to grow within the cell. Using these computer simulations, he hopes to predict how and why cells open their doors to these dangerous invaders.

“Our strength is bridging ‘in silico’ computer simulations with wet-lab experimental approaches,” says Yin who collaborated with fellow CU-�鶹ӰԺ biochemist and Biofrontiers Institute faculty member, Natalie Ahn, as well as CU-�鶹ӰԺ biologist, Jennifer Martin. Ahn provided her expertise in mass spectroscopy to understand the structure of the LMP-1 molecule. Martin is an expert on the Epstein-Barr virus and contributed her knowledge on the nature of the virus and how it causes cancer.

Yin’s next step is to take the data provided by the computer simulations of the membrane protein and use it to predict how it will react to potential drugs. It is even more difficult than it sounds. These proteins have defied exploration by many scientists before Yin. But these drugs may provide a process for treating HHV-4, and stopping deadly lymphomas in their tracks.

“Trying to achieve something that took nature millions of years to develop is an outstanding intellectual challenge,” says Yin. “And multidisciplinary approaches are the means we must take to approach this problem.”

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