The first comprehensive analysis of an animal's immune response to the 1918 influenza virus provides new insights into the killer flu, report federally supported scientists in an article appearing online in the journal "Nature." Key among these insights, they found that the 1918 virus triggers a hyperactive immune response that may contribute to the lethality of the virus. Furthermore, their results suggest that it is the combination of all eight of the 1918 flu virus genes interacting synergistically that accounts for the exceptional virulence of this virus.
Michael G. Katze, Ph.D., of the University of Washington School of Medicine, Seattle, a grantee of the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), led the research team with University of Washington's John Kash, Ph.D. The work with the fully reconstructed 1918 virus was conducted by coauthor Terrence Tumpey, Ph.D., in a biosafety level 3-enhanced laboratory at the US Centers for Disease Control and Prevention (CDC) in Atlanta.
"Understanding as much as possible about the virus that caused the devastating 1918-1919 influenza pandemic is an urgent imperative as we pursue efforts to prepare for -- and possibly thwart -- the next flu pandemic," says NIH Director Elias A. Zerhouni, M.D.
"This elegant research gives a detailed picture of the overzealous host reaction to infection by a fully reconstructed 1918 influenza virus," says NIAID Director Anthony S. Fauci, M.D. "The research provides clues as to why the flu of 1918 was so deadly, and may also help us better understand the disease process that occurs when people are infected by emerging avian influenza viruses, such as the H5N1 strain."
Unlike typical seasonal flu, which strikes hardest at the very young, the elderly and those with compromised immune function, the 1918 flu disproportionately killed young people in the prime of life. Modern analyses of 1918 flu victim autopsy samples show extreme and extensive damage to lung tissues. This observation gave rise to the hypothesis that the 1918 flu virus infection provoked an uncontrolled inflammatory response leading to rapid lung failure and death.
To test this idea, Dr. Tumpey infected mice intranasally with one of four types of flu virus: human seasonal flu virus from a strain that circulated in Texas in 1991; lab-made viruses containing either two or five of eight viral genes from the 1918 virus; or a reconstructed virus containing all eight 1918 flu virus genes. Lung tissue from three infected mice in each group was removed on days 1, 3 and 5 post-infection and processed to destroy any virus. The mouse genetic material (RNA) was then extracted from these lung samples and sent to the University of Washington team for analysis.
Drs. Katze and Kash and colleagues examined the mouse RNA using microarrays to determine which genes were activated when exposed to each of the four viruses. This analysis showed that the immune response to the reconstructed 1918 virus containing all eight flu genes was much greater than to any of the other viruses with all eight genes, says Dr. Katze. In particular, genes involved in promoting inflammation were strongly and immediately activated following infection by the reconstructed 1918 virus. "We clearly see a dramatic and uncontrolled immune response in the mouse lungs as early as one day following infection with the reconstructed 1918 virus," he says. A complete understanding of the host's response to the 1918 flu virus, adds Dr. Katze, requires use of a fully reconstructed virus.
A fuller picture of the host immune response to the 1918 flu virus could also be valuable to scientists working to develop therapies against such viruses as the H5N1 avian influenza, the researchers note. Besides targeting the flu virus itself, Dr. Katze explains, researchers might develop new or improved agents aimed at moderating or halting the human immune system's overactive response to these viruses.
In addition to Dr. Katze, other NIAID grantees contributing to this research included Christopher F. Basler, Ph.D., Peter Palese, Ph.D., and Adolfo García-Sastre, Ph.D., all of Mount Sinai School of Medicine, New York. Jeffery K. Taubenberger, M.D., Ph.D., formerly of the Armed Forces Institute of Pathology, Rockville, MD, and now of NIAID, is also a coauthor.
Besides support from NIAID, Dr. Katze, who is professor of microbiology at the University of Washington and Associate Director of Washington National Primate Center, also received grants from the National Center for Research Resources and from the National Institute on Drug Abuse, both components of NIH, for his research.