ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways

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Science Immunology  12 Aug 2016:
Vol. 1, Issue 2, pp. aag2045
DOI: 10.1126/sciimmunol.aag2045

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Sensing flu

People infected with influenza get sick not only because of the presence of virus but also because of the inflammatory immune response. Now, Kuriakose et al. report that the protein ZBP1/DAI (Z-DNA binding protein 1/DNA-dependent activator of IFN regulatory factors) senses influenza A virus (IAV) and may contribute to this inflammatory pathogenesis. They found that ZBP1/DAI triggered cell death and inflammatory responses after IAV infection, and that ZBP1/DAI deficiency protected mice from IAV-related mortality. These mice had decreased inflammation and less epithelial damage than control animals. If these findings hold true in humans, ZBP1/DAI may be a host-directed target to decrease the severity of IAV pathogenesis.


The interferon (IFN)–inducible protein Z-DNA binding protein 1 [ZBP1; also known as DNA-dependent activator of IFN regulatory factors (DAI) and DLM-1] was identified as a double-stranded DNA sensor, which instigates innate immune responses. However, this classification has been disputed, and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. We demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the receptor-interacting protein kinase 1 (RIPK1)–RIPK3–caspase-8 axis. ZBP1 regulates NLRP3 (nucleotide and oligomerization domain, leucine-rich repeat–containing protein family, pyrin domain containing 3) inflammasome activation as well as induction of apoptosis, necroptosis, and pyroptosis in IAV-infected cells. ZBP1 deficiency protected mice from mortality during IAV infection owing to reduced inflammatory responses and epithelial damage. Overall, these findings indicate that ZBP1 is an innate immune sensor of IAV and highlight its importance in the pathogenesis of IAV infection.

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