? DESCRIPTION (provided by applicant): In this application, we will test the hypothesis that the Bcl6 gene, specifically in macrophages, inhibits host antiviral immunity and promotes host susceptibility to influenza virus infection. We will also explore whether the inhibition of Bcl6 function will enhance host anti-viral immunity to influenza and ameliorate severe host diseases during influenza virus infection. Two specific aims have been proposed. Specific Aim 1: To elucidate the underlying mechanisms by which Bcl6 deletion in macrophages attenuates influenza virus infection. Specific Aim 2: To determine if the inhibition of Bcl6 expression and/or function promotes macrophage IFN production and increase host resistance to influenza virus infection. The successful completion of this application will not only shed light on novel mechanisms of influenza pathogenesis and immune protection, but also open the door to developing novel therapeutic modalities against influenza infection in the near future. Relevance statement Seasonal influenza kills ~500,000 people globally and up to 50,000 people in the United States each year. In addition to seasonal outbreaks, pandemic influenza viruses occasionally emerge when humans are introduced to a virus to which they are immunologically naïve. Over the last decade, highly pathogenic avian influenza viruses (H5N1, H7N9) have emerged and recent data have highlighted the serious threat of another potential devastating influenza pandemic involving highly pathogenic virus strains. Current strategies for influenza prevention and treatment include yearly vaccination and anti-viral drugs. However, frequent changes in the surface antigens of influenza virus allow influenza viruses to escape antibody-mediated immune protection following vaccination and many circulating influenza virus strains have developed resistance to the current antiviral drugs. Thus, there is urgent need to understand the pathophysiology and the protective immune responses to influenza virus infection for the development of future preventive and therapeutic approaches. We believe that the novel method we employ here may provide alternative therapeutic modalities to those influenza virus strains that have already developed resistance to current anti-viral drugs.