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Toll\u2010like receptor 3 (TLR3) via TIR\u2010domain\u2010containing adapter\u2010inducing interferon\u2010\u03b2 (TRIF), Z\u2010DNA\u2010binding protein 1 (ZBP1) and tumor necrosis factor (TNF)\u03b1 mediate necroptosis, with ZBP1 and TNF playing pivotal roles in controlling viral infections, with the role of TLR3\u2013TRIF being less clear. ZBP1\u2010mediated necroptosis is initiated when host ZBP1 senses viral Z\u2010form double stranded RNA and recruits receptor\u2010interacting serine\/threonine\u2010protein kinase 3 (RIPK3), driving a mixed lineage kinase domain\u2010like pseudokinase (MLKL)\u2010dependent necroptosis pathway, whereas TNF\u2010mediated necroptosis is initiated by TNF signaling, which drives a RIPK1\u2013RIPK3\u2013MLKL 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\u2206Z\u03b1, trigger ZBP1\u2010dependent necroptosis in mouse embryonic fibroblasts. By contrast, when bone\u2010marrow\u2010derived macrophages are infected with the viruses, necroptosis is initiated predominantly through the TNF\u2010mediated pathway. However, when the TNF pathway is blocked by RIPK1 inhibitors or a TNF blockade, ZBP1\u2010mediated necroptosis becomes the prominent pathway in bone\u2010marrow\u2010derived macrophages. Overall, these data implicate a cell\u2010type preference for either TNF\u2010mediated or ZBP1\u2010mediated 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\u2010specific reactions that could alter the balance of inflammation versus control of virus, impacting the organism as a whole.<\/jats:p>","DOI":"10.1111\/febs.17045","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T12:08:51Z","timestamp":1703506131000},"page":"2388-2404","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cell\u2010type dependence of necroptosis pathways triggered by viral infection"],"prefix":"10.1111","volume":"291","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3061-9942","authenticated-orcid":false,"given":"Heather","family":"Koehler","sequence":"first","affiliation":[{"name":"School of Molecular Biosciences and Center for Reproductive Biology Washington State University  Pullman WA USA"},{"name":"College of 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