INFLUENZA MODEL
The looming threat of a new influenza pandemic, particularly one that evolves out of the highly pathogenic H5N1 avian influenza strains now circulating in many parts of the world, has prompted the use of macaque infection models to better understand influenza pathogenesis and to improve rapid diagnostic, therapeutic, and vaccine strategies. Macaque genomic and proteomic resources are central to maximizing the gains to be realized from this animal model.
Our most recent studies have focused on the influenza virus that caused the devastating 1918 "Spanish flu" pandemic, which resulted in an estimated 50 million deaths worldwide. In collaboration with Dr. Yoshihiro Kawaoka (University of Wisconsin) and Dr. Heinz Feldman (Special Pathogens Program, National Microbiology Laboratory, Winnipeg, Canada), we evaluated the host response to the reconstructed 1918 virus using a cynomolgus macaque (Macaca fascicularis) infection model (Kobasa et al., Nature 445:319-323, 2007). This study revealed that the 1918 virus replicated to high levels and spread rapidly throughout the respiratory tract of infected animals, causing severe damage and massive infiltration of immune cells. Functional genomics analyses revealed that the 1918 virus triggered unusually high and sustained expression of numerous genes involved in the innate immune response, including those encoding proinflammatory cytokines and chemokines.
This study also demonstrated similarities and differences in the host response to contemporary and pandemic influenza virus infection. The 1918 and contemporary viruses each triggered an innate immune response that included the expression of NF-kB and IRF-3 target genes and both viruses triggered a robust cytokine response that likely attracted immune cell infiltration to infected tissues. However, unlike the innate immune response triggered by contemporary strain, the response triggered by the 1918 virus was strong and sustained and was associated with massive tissue damage and death. Importantly, a strong and sustained induction of the innate immune response also appears to be a hallmark feature of H5N1 avian influenza virus infection of humans, in which the case-fatality rate is greater than 50%. Our studies of the 1918 virus may therefore provide important clues into what makes H5N1 influenza viruses highly pathogenic.