NCRR Reporter - Winter 2010 - Research Brief

To study how bodies react to influenza, Michael Katze, associate director of the NCRR-funded Washington National Primate Research Center, uses a mass spectrometer and other technologies to investigate the immune responses of monkeys to flu viruses. Photo courtesy of the Washington National Primate Research Center

Research Brief
Decoding the Pandemic Puzzle
In the past decade, two influenza viruses have caused widespread concern about a possible pandemic that could be as deadly as the 1918 flu—responsible by some estimates for up to 100 million deaths worldwide. Fortunately, neither recent threat has caused nearly as much damage. One, the current strain of H1N1 "swine flu," swept the globe but has caused relatively mild symptoms and fewer deaths than feared. The other, H5N1 "bird flu," has been far deadlier but slower to spread from person to person.

Researchers across the globe, including many supported by NCRR, are investigating how these two emerging viruses have caused such varying effects in humans and how both differ from the 1918 pandemic virus—a different H1N1 strain—and from seasonal flu. The ultimate goal is to protect populations from a virus with H1N1's infectivity and H5N1's lethality.

The key is to understand the variations not only in the viruses but also in how infected bodies respond to them, said Michael Katze, associate director of the NCRR-funded Washington National Primate Research Center (WaNPRC). To find out, Katze and a team of leading NIH-supported scientists are examining the immune responses of monkeys to various flu viruses. The team includes renowned influenza virologist Yoshihiro Kawaoka of the University of Wisconsin–Madison and the University of Tokyo as well as Richard Smith of the Pacific Northwest National Laboratory (PNNL), an expert in the field of proteomics—the large-scale study of how proteins function.

This team already has shown that the 1918 flu was so deadly because it caused an unusually strong immune response. In 2007, Katze, Kawaoka and their collaborators reported in Nature that macaque monkeys infected with the 1918 virus mounted a stronger and more prolonged immune response than did macaques infected with a weaker flu. The 1918 virus, the researchers discovered, makes the immune system attack the body, and this response causes inflammation and fills the lungs with fluid. "The resulting damage is devastating," Katze said

The team's approach, examining both the virus and the response it generates, fits neatly into the growing interdisciplinary field of systems biology. This field explores how individual components work together to create a complex biological "system"—a cell, a tissue or an organism.

The goal, according to Katze, is to find differences in how bodies respond to mild and severe pathogens and then to exploit those variations. Traditional antiviral medications interfere with a virus' internal workings; this new view of virus-host interactions could produce therapies that instead either amplify or diminish the body's immune response to a virus.

To gain a better understanding of this response, the team turned to Smith for his expertise and access to sophisticated equipment that can analyze the body's inner workings. At PNNL, Smith directs the Proteomics Research Resource for Integrative Biology, one of NCRR's Biomedical Technology Resource Centers. These centers develop techniques and methods to advance basic and translational research. With additional NCRR funding provided through the American Recovery and Reinvestment Act to the WaNPRC, Katze and Smith are working to develop databases of genetic and protein information for macaques, including virus-induced changes in protein levels.

The result should provide "a nearly comprehensive view of a host's response to infection," Katze said. The entire research community will be able to use this new information to improve studies of these deadly viruses.

Katze and Smith think that studying monkeys, rather than more distantly related mice and rats, is the best way to understand the human virus response. Their work at WaNPRC receives support from NCRR's National Primate Research Center program, which provides funding for animals, facilities and technologies. Katze and Kawaoka's work in influenza also receives support from the National Institute of Allergy and Infectious Diseases.

The researchers hope to develop new therapies and perhaps even strategies for vaccines based on their understanding of how bodies respond to influenza infection. The accomplishments so far, Smith said, represent "just the smallest tip of the iceberg. The next few years look to be tremendously exciting as this story is revealed."

— Lila Guterman and Aimee Swartz


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NCRR Reporter - Winter 2010 - Research Brief