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Influenza virus induces apoptosis in infected cells to promote viral replication by manipulating the host cell death signaling pathway. Although some Bcl-2 family proteins play a role in the replication of influenza A virus (IAV), the role of cell death pathways in the viral replication cycle is unclear. We investigated whether deficiency of the proapoptotic Bcl-2 family protein, Bik, plays a role in IAV replication. IAV replication was attenuated in mouse airway epithelial cells (MAECs) from bik-/- compared with bik+/+ mice, as indicated by reduced viral titers. Bik-/- MAECs showed more stable transepithelial resistance after infection than did bik+/+ MAECs, were less sensitive to infection-induced cell death, and released fewer copies of viral RNA. Similar results were obtained when Bik expression was suppressed in human airway epithelial cells (HAECs). Bik+/+ mice lost weight drastically and died within 8 days of infection, whereas 75% of bik-/- mice survived infection for 14 days and were 10-fold less likely to die from infection compared with bik+/+ mice. IAV infection activated caspase 3 in bik+/+ but not in bik-/- MAECs. Cleavage of viral nucleoprotein and M2 proteins were inhibited in bik-/- MAECs and when caspase activation was inhibited in HAECs. Furthermore, Bik deficiency impaired cytoplasmic export of viral ribonucleoprotein. These studies suggest a link between Bik-mediated caspase activation and cleavage of viral proteins. Thus, inhibition of proapoptotic host factors such as Bik and downstream mediators of cell death may represent a novel approach to influenza treatment.