The long term goal of this project is to define molecular mechanisms by which influenza A viruses kill cells. Influenza A viruses continue to cause significant disease problems in humans, lower mammals and birds; however, the mechanism(s) by which these viruses kill host cells remains undefined. Our own studies have focused on an avian model to examine influenza pathogenesis, using a highly virulent strain, A/Ty/Ont/7732/66 (Ty/Ont) which rapidly produces devastating disease in birds, including severe lymphoid depletion. Our recent studies demonstrate that Ty/Ont replicates and induces apoptosis in a chicken lymphocyte cell line, reflective of the in vivo infection. We extended these studies to the mammalian system and discovered that the human virus, A/PR/8/34 (PR/8), as well as Ty/Ont and other influenza strains, induces apoptosis in the mammalian cell line, Madin-Darby canine kidney (MDCK). These findings suggest that apoptosis is a general mechanism of influenza virus-induced cell death. In support of this idea, our preliminary studies indicate that apoptosis by these viruses is prevented by bcl-2, a cellular oncogene involved in suppressing apoptosis. The specific aims are to: 1. Examine the cellular pathways involved in influenza virus-induced apoptosis. 2. Determine the role of specific influenza viral genes in apoptosis. 3. Define specific regions of viral gene(s) involved in apoptosis in vivo and in vitro. The information gained from addressing these specific aims will identify the role of specific cellular and viral genes in cell death. This offers a unique opportunity to obtain information basic to understanding influenza virus pathogenesis, as well as apoptosis.