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

Teneema Kuriakose, Si Ming Man, R. K. Subbarao Malireddi, Rajendra Karki, Sannula Kesavardhana, David E. Place, Geoffrey Neale, Peter Vogel, Thirumala Devi Kanneganti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

507 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numberaag2045
JournalScience immunology
Volume1
Issue number2
DOIs
Publication statusPublished - 2016
Externally publishedYes

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