title: ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways.
abstract: The interferon-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 dsDNA 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. Herein, we demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the RIPK1-RIPK3-Caspase-8 axis. ZBP1 regulates NLRP3 inflammasome activation as well as induction of apoptosis, necroptosis and pyroptosis in IAV-infected cells. Importantly, 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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Teneema
authors.initials: T
authors.lastname: Kuriakose
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Si Ming
authors.initials: SM
authors.lastname: Man
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: R K Subbarao
authors.initials: RK
authors.lastname: Malireddi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Karki
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Sannula
authors.initials: S
authors.lastname: Kesavardhana
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Place
authors.affiliation: Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
keywords: DAI; IFNs; NLRP3; RIPK3; ZBP1; apoptosis; caspase-1; caspase-8; inflammasome; influenza virus; necroptosis; pyroptosis