Thesis

Impact of influenza virus replication on the IFN-γ Response in macrophages

Macrophages are important for protection against infection with influenza viruses, they may also contribute to disease severity during H5N1 influenza virus infection through the virus induced alteration of important antiviral functions. One reason for these changes might be due to the ability of H5N1 viruses to replicate efficiently in the macrophage. Thus, we hypothesized that H5 virus infection alters the macrophage antiviral response and abrogates the IFN-γ response in RAW264.7 macrophages in a replication dependent manner. Infection of macrophage with live H5 virus decreased the phagocytic activity of IFN-γ activated RAW264.7 cells. Similarly, a reduction in nitric oxide (NO) production was also observed in IFN-γ activated macrophages infected with live H5 virus. Interestingly, infection with UV-inactivated H5 virus restored the phagocytic activity and NO production of IFN-γ activated macrophages. This shows that replication of H5 influenza virus is critical and is required to evade the macrophage antiviral response. H5 virus interferes with these macrophage functions by inhibiting IFN-γ signaling. While tyrosine phosphorylation of STAT1 was found to be intact in IFN-γ activated macrophages infected with H5 virus, expression of the IFN-γ stimulated gene IRF-1 was, blocked. Thus H5 influenza virus alters the antiviral response of macrophages and antagonize the IFN-γ response in macrophages in a replication dependent manner.

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