Vaccines

Flu researchers discover new mechanism for battling influenza

Anonymous — Thu, 02 Nov 2017 06:00:00 +0000

Flu researchers discover new mechanism for battling influenza Anonymous (not verified) Thu, 11/02/2017 - 00:00

Lisa Marshall

Just as flu season swings into full gear, researchers from the University of babyֱ��app Boulder and University of Texas at Austin have uncovered a previously unknown mechanism by which the human immune system tries to battle the influenza A virus. The discovery sheds new light on how the virus — which kills 12,000 to 56,000 people in the United States annually — often wins, and it could ultimately lead to new treatments.

“We’ve solved a mystery, revealing a new aspect of our innate immune system and what flu has to do to get around it,” says Nicholas Meyerson, a postdoctoral researcher in the BioFr ontiers Institute and lead author of a paper published in the Nov. 8 issue of Cell Host and Microbe.

The findings, several years in the making, could lead to a better understanding of how the seasonal flu virus, which typically originates in birds, makes its way to humans. They could also inform development of next-generation antivirals able to combat a broad spectrum of influenza strains, says co-senior author Robert Krug, a leading influenza researcher and professor at the University of Texas at Austin.

The paper focuses on two key molecular players in the story of influenza infection: a human protein called TRIM25, which was recently discovered to play an important role in the human immune response to flu infection; and a protein called NS1 present in all strains of the influenza A virus and shown to bind TRIM25 to keep it from doing its job.

“We were basically trying to find out what TRIM25 was doing that flu did not want it to be doing and the role NS1 was playing in blocking that function,” Krug said.

Through a series of laboratory tests, the team revealed two main findings:

TRIM25 acts earlier than previously believed, latching on to a critical and unique flu virus structure like a “molecular clamp” to keep the virus from replicating as soon as TRIM25 detects this unique structure.

NS1 produced by the flu virus can block this function of TRIM25, enabling flu to circumvent the immune response and cause infection.

Previous research had suggested that TRIM25 fought off flu by switching on what is known as the “interferon response” — a complex signaling pathway that arms cells through the body to fight off pathogens. But not all strains of influenza block this interferon signaling pathway, which led Meyerson to suspect another mechanism was at play in helping TRIM25 fight flu.

The paper reveals that TRIM25 is also a “restriction factor,” a special protein present in the fastest-acting arm of the immune system, before spreading infection occurs.

“Restriction factors lie in wait, and should a virus be detected in one of your cells, they have immediate destructive ability,” explains co-senior author Sara Sawyer, an associate professor of Molecular, Cellular and Developmental Biology (MCDB) at CU Boulder.

Flu uses its NS1 protein to evade TRIM25’s early flu-fighting response, the researchers found.

To do the study, the researchers first infected transgenic cell lines loaded with nonhuman primate versions of TRIM25 with the human influenza A virus. They found that the cells fought off the virus far better than human versions of the TRIM25 protein.

“This told us that TRIM25 has the capacity to crush influenza, but that its human form was less active,” Meyerson said.

To find out how it crushes influenza, the researchers combined purified TRIM25 with purified viral ribonucleoproteins (vRNPs) — eight-piece protein chains that house the influenza genome — and used state-of-the-art electron microscopy to take pictures of what happened.They found that TRIM25 appears to swiftly recognize the unique structure of vRNPs and clamps down on them to keep them from replicating inside the cell.Other experiments confirmed that the NS1 protein in flu virus inhibits this function.

They also found that TRIM25 (previously believed to be present only in the cell cytoplasm) is also present in the cell nucleus, which is the same cellular location where flu replication occurs.

Sawyer and Meyerson are now looking to further investigate the role TRIM25 plays in cross-species transmission of influenza.

More studies are needed, but Krug believes new therapeutics could be designed to block the NS1 protein produced by the flu virus, hobbling its ability to evade the human immune system.

“If you could somehow block NS1 from acting, you could block all strains of the virus,” he says.

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$1.1 million grant funds CU Boulder research into next-generation vaccines

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

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

BioFrontiers

The University of babyֱ��app Boulder 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 Boulder, 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-Boulder’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 Boulder and the BioFrontiers Institute. At the University of babyֱ��app 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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Tracking malaria's evolution

Anonymous — Mon, 12 Oct 2015 06:00:00 +0000

Tracking malaria's evolution Anonymous (not verified) Mon, 10/12/2015 - 00:00

BioFrontiers

A new paper published Nature Communications, coauthored by a researcher at the University of babyֱ��app’s BioFrontiers Institute, looked at the genetic strategy used by the human malaria parasite and how old it is from an evolutionary perspective. BioFrontiers’ Aaron Clauset, an assistant professor of computer science, was part of a team that analyzed genetic data from apes and found that the genetic strategy used by the parasites that cause a malaria infection is the same, whether the disease is in humans or other primates. The team compared the genes of ape malaria parasites with those of human malaria to determine if the two use the same strategies for prolonging the disease.

Malaria is a complex disease process where the parasite invades red blood cells and the disease produces proteins on the cell’s surface. Genes called “var genes” create these proteins, which are recognized by the immune system’s antibodies. These antibodies bind onto the cell surface then kill the cell that contains the parasite. To confuse the host’s immune system, the parasite switches the types of var genes it uses on the surface of the cell so that antibodies can’t bind with the cell surface and kill the host cell and parasite. In addition, the parasite’s var genes, once they are in the cell, mix genetic information in a process called recombination so that antibodies are faced with an almost infinite number of different proteins the prevent the host cell from being killed.

The study, led by Daniel Larremore, an Omidyar Fellow at the Santa Fe Institute and a researcher at the Center for Communicable Disease Dynamics (CCDD) and the Department of Epidemiology at Harvard School of Public Health, used fecal and blood samples from wild chimpanzees and western lowland gorillas, as well as chimpanzees living in a sanctuary to better understand the patterns in the var genes. They looked at similarities between the genes that are implicated with severe malaria in humans and those in other primate malaria parasites. The fecal and blood samples were leftover samples collected for previous genetic studies.

The team analyzed a small region of the gene sequence using network techniques and identified patterns that were consistent across different types of primate malaria parasites. The research team analyzed 369 new sequence fragments from ape parasite species of wild living and sanctuary apes and added 353 previously known sequences. Larremore received his PhD in applied math from CU-Boulder. After receiving his PhD, he had a joint postdoctoral position in Clauset’s lab and Harvard’s CCDD.

“Malaria is an important system to work on,” says Clauset. “It’s both a major public health issue, especially in developing countries and places where climate change is bringing it back, and a fascinating evolutionary system. The malaria parasite has an ever-changing bag of genetic tricks it uses to prolong an infection, and understanding how it does this will help develop better treatments for this disease and help us understand how some other diseases, like HIV, maintain their evolvability over long periods of time. ”

Malaria is difficult to treat in humans because the malaria parasite has an extensive and ever-changing set of tricks to avoid detection by the immune system. Apes, humans, and even birds and reptiles, have their own version of malaria. This study showed that malaria in all primates (including humans) use the same genetic system to evolve new ways to avoid detection by the host's immune system. The wild primate blood samples showed several strains of malaria. Because the disease evolved with primates, their immune systems are equipped to manage it so it causes fewer, less severe symptoms. Humans suffer much more severe symptoms than primates, and even death, from the disease. The researchers believe this is because malaria jumped from primates to humans after the two split from a common ancestor: Human immune systems have had less time to evolve to manage the disease.

“Our results show that human malaria uses the same genetic strategy as ape malaria to prolong an infection. This insight may help us identify components of this immune evasion system that could become targets for a vaccine,” says Clauset. “It may also help us understand other diseases that use similar strategies, like the pneumococcus and HIV.”

The study was supported by grants from the National Institutes of Health and the Wellcome Trust.

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Nanoly wins 2014 Tech Award

Anonymous — Tue, 18 Nov 2014 07:00:00 +0000

Nanoly wins 2014 Tech Award Anonymous (not verified) Tue, 11/18/2014 - 00:00

BioFrontiers

CU-Boulder startup wins Silicon Valley Tech Award for vaccine innovation that will save lives around the world

Photo: Balaji Sridhar's company, Nanoly Bioscience, recently won a Tech Award. He works in Kristi Anseth's lab as a PhD candidate in Chemical Engineering.

Balaji Sridhar is a Chemical Engineering PhD candidate at the University of babyֱ��app Boulder. He is halfway through two years of the Medical Scientist Training Program that is a joint effort between CU campuses in Denver and Boulder, and he will head back to medical school after receiving his PhD degree. He is also leading a company that aims to save millions around the world who die from vaccine-preventable diseases. Sridhar is headed home after a week-long stay in Silicon Valley where he accepted the Katherine M. Swanson Young Innovator Award for his company, Nanoly Bioscience, Inc. The Tech Awards, given by The Tech Museum of Innovation, honors innovators from around the world who are applying technology to benefit humanity, and Sridhar is already working toward that goal.

The World Health Organization estimates that 2.1 million people die each year from vaccine-preventable diseases. In addition, a significant fraction of vaccines never make it to patients due to temperature spoilage. Nanoly Bioscience is working to bypass the vaccine “cold chain,” which is a refrigerated system of transporting and storing vaccines within the narrow temperature range of 35 to 45 degrees Fahrenheit. The strict temperature limitations are necessary to prevent vaccine proteins from denaturing, rendering the vaccines inactive. Keeping vaccines at a certain temperature restricts their ability to be delivered to remote areas of the world where there is no electricity or refrigeration – areas that could benefit from vaccines the most.

“We are developing a polymer that can be blended with vaccines to prevent spoilage without refrigeration,” says Sridhar. “The polymer is non-toxic, and exposure to light will disassemble the polymer so that the vaccine is ready for delivery."

Nanoly was one of ten teams from around the world selected for the Tech Awards. Each team receives cash prizes from the awards’ major sponsors and Sridhar also spent part of the week meeting with mentors and venture capital investors about the company’s vaccine polymer.

BioFrontiers’ Associate Director, Kristi Anseth, a Distinguished Professor of Chemical and Biological Engineering and a Howard Hughes Medical Investigator, is one of four advisers for Nanoly Bioscience. The company nucleated in Anseth’s lab in the Jennie Smoly Caruthers Biotechnology Building at the University of babyֱ��app in Boulder. Anseth continues to support the scientific development of the new company.

“Nanoly is a great example of what we are trying to do in my lab, at BioFrontiers and in this building,” says Anseth. “We want to empower scientists to work across disciplines, give them access to technology and resources, and support their entrepreneurial work. This is a new way of bridging the gap between academics and industry, one that engages students and enables them to pursue independent ideas, so that we can get technologies like this one out into the world faster.”

More information on Nanoly Bioscience, Inc. can be found on their website or on Twitter.

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