Programmed Necrosis in Host Defense

Host control over infectious disease relies on the ability of cells in multicellular organisms to detect and defend against pathogens to prevent disease. Evolution affords mammals with a wide variety of independent immune mechanisms to control or eliminate invading infectious agents. Many pathogens acquire functions to deflect these immune mechanisms and promote infection. Following successful invasion of a host, cell autonomous signaling pathways drive the production of inflammatory cytokines, deployment of restriction factors and induction of cell death. Combined, these innate immune mechanisms attract dendritic cells, neutrophils and macrophages as well as innate lymphoid cells such as natural killer cells that all help control infection. Eventually, the development of adaptive pathogen-specific immunity clears infection and provides immune memory of the encounter. For obligate intracellular pathogens such as viruses, diverse cell death pathways make a pivotal contribution to early control by eliminating host cells before progeny are produced. Pro-apoptotic caspase-8 activity (along with caspase-10 in humans) executes extrinsic apoptosis, a nonlytic form of cell death triggered by TNF family death receptors (DRs). Over the past two decades, alternate extrinsic apoptosis and necroptosis outcomes have been described. Programmed necrosis, or necroptosis, occurs when receptor interacting protein kinase 3 (RIPK3) activates mixed lineage kinase-like (MLKL), causing cell leakage. Thus, activation of DRs, toll-like receptors (TLRs) or pathogen sensor Z-nucleic acid binding protein 1 (ZBP1) initiates apoptosis as well as necroptosis if not blocked by virus-encoded inhibitors. Mammalian cell death pathways are blocked by herpesvirus- and poxvirus-encoded cell death suppressors. Growing evidence has revealed the importance of Z-nucleic acid sensor, ZBP1, in the cell autonomous recognition of both DNA and RNA virus infection. This volume will explore the detente between viruses and cells to manage death machinery and avoid elimination to support dissemination within the host animal.