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Title: GENOMIC ANALYSIS OF INCREASED HOST IMMUNE AND CELL DEATH RESPONSES BY 1918 INFLUENZA VIRUS

Author
item KASH, JOHN - UNIV OF WA-SEATTLE, WA
item TUMPEY, TERRENCE - INFLU BR-CDC-ATLANTA,GA
item PROLL, SEAN - UNIV OF WA-SEATTLE, WA
item CARTER, VICTORIA - UNIV OF WA-SEATTLE, WA
item PERWITISARI, OLIVIA - UNIV OF WA-SEATTLE, WA
item THOMAS, MAATTHEW - UNIV OF WA-SEATTLE, WA
item BASLER, CHRISTOPHER - MT SINAI-NEW YORK, NY
item PALESE, PETER - MT SINAI-NEW YORK, NY
item Swayne, David
item TAUBENBERGER, JEFFREY - ARMED FORCES INST-MD
item GARCIA-SASTRE, ADOLFO - MT SINAI-NEW YORK, NY
item KATZE, MICHAEL - UNIV OF WA-SEATTLE, WA

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/18/2006
Publication Date: 9/27/2006
Citation: Kash, J.C., Tumpey, T.M., Proll, S.C., Carter, V., Perwitisari, O., Thomas, M.J., Basler, C.F., Palese, P., Swayne, D.E., Taubenberger, J.K., Garcia-Sastre, A., Katze, M.G. 2006. Genomic analysis of increased host immune and cell death responses by 1918 influenza virus. Nature. 443(7111):578-581.

Interpretive Summary: The 1918-19 Spanish flu killed 20-40 million people with severe lung lesions. The mechanism of the lung damage is unknown. This study demonstrated that the 1918 virus in a mouse model has severe lung lesions with more rapid activation of pro-inflammatory processes and cell death. Better understanding of the host response is a starting point for identification of predictors of disease severity and development of therapies.

Technical Abstract: The influenza pandemic of 1918-19 was responsible for in excess of 20-40 million deaths worldwide and is believed to potentially originate from introduction of a novel avian virus into humans. The disease reported in 1918-19 consisted of a severe, rapidly progressive pneumonia with severe pulmonary necrosis and edema. Modern histopathological analysis of autopsy samples from human 1918 influenza cases revealed significant damage to the lungs with acute, focal bronchitis and alveolitis associated with massive pulmonary edema, hemorrhage and rapid destruction of the respiratory epithelium. The contribution of the host immune response leading to this severe pathology remains largely unknown. Here we show that mice infected with the reconstructed 1918 influenza virus displayed severe pulmonary pathology associated with an increased and accelerated activation of immune responses. We found that mice infected with a virus containing all eight genes from the pandemic virus showed dramatic activation of pro-inflammatory and cell death pathways beginning by 24h post-infection that remained unabated until death on day 5. This was in contrast to infection with influenza viruses containing subsets of 1918 genes that displayed less severe disease pathology, delays in death, and lessened immune responses. These results suggest a cooperative interaction between the 1918 influenza genes and demonstrated that study of the virulence of the 1918 influenza virus requires use of the fully reconstructed 1918 virus. With recent concerns about the introduction of highly pathogenic avian influenza viruses into humans and their potential to cause a world-wide epidemic with disastrous health and economic consequences, a comprehensive analysis of the global host response to the 1918 virus is critical. Moreover, understanding the contribution of host immune responses to influenza virus is an important starting point for the identification of prognostic indicators and the development of novel antiviral therapies.