Cell-type dependence of necroptosis pathways triggered by viral infection
Heather Koehler1,2,3, Derek Titus3,4, Crystal Lawson1,2,3
1School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA, USA.
Abstract:
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.
Insights
Necroptosis, a programmed cell death, uses Z-DNA-binding protein 1 (ZBP1) or tumor necrosis factor (TNF) pathways to fight viruses. Cell type dictates which necroptosis pathway is dominant, influencing host defense against infection.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- Necroptosis is a crucial host defense mechanism against viral infections.
- Three pathways initiate necroptosis: Toll-like receptor 3 (TLR3)-TIR-domain-containing adapter-inducing interferon-β (TRIF), Z-DNA-binding protein 1 (ZBP1), and tumor necrosis factor (TNF)α.
- ZBP1 and TNF pathways are key in controlling viral infections, while the TLR3-TRIF role is less understood.
Purpose of the Study:
- To investigate the distinct roles and cell-type specific activation of ZBP1-mediated and TNF-mediated necroptosis pathways during viral infections.
- To understand how viruses evade host defense mechanisms and how engineered viruses can trigger specific necroptosis pathways.
Main Methods:
- Utilized engineered viruses lacking viral inhibitors of programmed cell death (murine cytomegalovirus M45mutRHIM and vaccinia virus E3∆Zα).
- Infected mouse embryonic fibroblasts and bone-marrow-derived macrophages with engineered viruses.
- Blocked TNF signaling using RIPK1 inhibitors or TNF blockade to assess pathway dominance.
Main Results:
- Engineered viruses triggered ZBP1-dependent necroptosis in mouse embryonic fibroblasts.
- In bone-marrow-derived macrophages, necroptosis was predominantly initiated via the TNF-mediated pathway.
- Blocking the TNF pathway shifted necroptosis initiation to the ZBP1-mediated pathway in macrophages.
Conclusions:
- Host cells exhibit a preference for either TNF-mediated or ZBP1-mediated necroptosis pathways in response to viral infections.
- These cell-type specific preferences are critical for understanding host-virus interactions and developing accurate disease models.
- Considering these pathway preferences is essential for evaluating the balance of inflammation and viral control in vivo.
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