ZBP1/DAI-Dependent Cell Death Pathways in Influenza A Virus Immunity and Pathogenesis

Influenza A viruses (IAV) are members of the Orthomyxoviridae family of negative-sense RNA viruses. The greatest diversity of IAV strains is found in aquatic birds, but a subset of strains infects other avian as well as mammalian species, including humans. In aquatic birds, infection is largely restricted to the gastrointestinal tract and spread is through feces, while in humans and other mammals, respiratory epithelial cells are the primary sites supporting productive replication and transmission. IAV triggers the death of most cell types in which it replicates, both in culture and in vivo. When well controlled, such cell death is considered an effective host defense mechanism that eliminates infected cells and limits virus spread. Unchecked or inopportune cell death also results in immunopathology. In this chapter, we discuss the impact of cell death in restricting virus spread, supporting the adaptive immune response and driving pathogenesis in the mammalian respiratory tract. Recent studies have begun to shed light on the signaling pathways underlying IAV-activated cell death. These pathways, initiated by the pathogen sensor protein ZBP1 (also called DAI and DLM1), cause infected cells to undergo apoptosis, necroptosis, and pyroptosis. We outline mechanisms of ZBP1-mediated cell death signaling following IAV infection.