Cell‐type dependence of necroptosis pathways triggered by viral infection

Necroptosis, a potent host defense mechanism, limits viral replication and pathogenesis through three distinct initiation pathways. Toll‐like receptor 3 (TLR3) via TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF), Z‐DNA‐binding protein 1 (ZBP1) and tumor necrosis factor (TNF)α mediate necroptosis, with ZBP1 and TNF playing pivotal roles in controlling viral infections, with the role of TLR3–TRIF being less clear. ZBP1‐mediated necroptosis is initiated when host ZBP1 senses viral Z‐form double stranded RNA and recruits receptor‐interacting serine/threonine‐protein kinase 3 (RIPK3), driving a mixed lineage kinase domain‐like pseudokinase (MLKL)‐dependent necroptosis pathway, whereas TNF‐mediated necroptosis is initiated by TNF signaling, which drives a RIPK1–RIPK3–MLKL pathway, resulting in necroptosis. Certain viruses (cytomegalovirus, herpes simplex virus and vaccinia) have evolved to produce proteins that compete with host defense systems, preventing programmed cell death pathways from being initiated. Two engineered viruses deficient of active forms of these proteins, murine cytomegalovirus M45mutRHIM and vaccinia virus E3∆Zα, trigger ZBP1‐dependent necroptosis in mouse embryonic fibroblasts. By contrast, when bone‐marrow‐derived macrophages are infected with the viruses, necroptosis is initiated predominantly through the TNF‐mediated pathway. However, when the TNF pathway is blocked by RIPK1 inhibitors or a TNF blockade, ZBP1‐mediated necroptosis becomes the prominent pathway in bone‐marrow‐derived macrophages. Overall, these data implicate a cell‐type preference for either TNF‐mediated or ZBP1‐mediated necroptosis pathways in host responses to viral infections. These preferences are important to consider when evaluating disease models that incorporate necroptosis because they may contribute to tissue‐specific reactions that could alter the balance of inflammation versus control of virus, impacting the organism as a whole.