Researchers have come another step closer to understanding what made the influenza strain of 1918 virus so devastating. In this week's issue of Nature, a team of scientists describes for the first time what happens at the genomic level in animals infected with the killer virus. The infection rapidly turned on a wide range of genes involved in immune system activation and cell death, they conclude, bolstering the hypothesis that the greatest harm may not have been done by the virus itself, but by an over-reactive immune system.
The paper is the latest in a series of studies using the 1918 influenza virus, which a research team led by Jeffery Taubenberger of the Armed Forces Institute of Pathology in Washington, D.C., pieced together over many years from snippets of genetic material. In a paper published last year, the group characterized the resurrected strain and its devastating impact on mice (ScienceNOW, 5 October 2005). For the current study, the same researchers teamed up with John Kash and Michael Katze of the University of Washington School of Medicine in Seattle, who study virus infection and host response at the genomic level. "We wanted to get at the mechanism behind the effects they saw," Kash says.
The team infected mice with the 1918 virus, a modern human flu strain, and hybrids of the two in which either two or five of influenza's eight genes came from the 1918 virus. Then they studied the mice's lungs microscopically and, using microarrays, measured the expression of many dozens of genes in their lung tissue at 1, 3, and 5 days after infection.
The 1918 virus jiggered many more genes into action than did the modern virus and the two hybrid strains, confirming the conclusion from last year's studies that it's not a single gene, but the action of all eight combined that made the 1918 virus so powerful. Most of the "upregulated" genes produce compounds known to activate immune cells--so-called cytokines and chemokines--or are involved in programmed cell death. That suggests that the damage done to the lungs is the result of an overreaction of the host, rather than the virus killing cells, Kash says.
David Relman, whose lab at Stanford University studies host reaction to infections as well, has some qualms about the team's methodology; for instance, he wonders if their results could be due to the fact that different cell types are present in the lungs during a severe infection, rather than to true differences in gene expression. But the study does suggest that dampening the so-called "cytokine storm"--which researchers believe is the culprit in several other viral infections as well--might be an additional strategy in the fight against viruses, he says.
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