Influenza A viruses limit NLRP3‐NEK7‐complex formation and pyroptosis in human macrophages |
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Authors: | Inês BoalCarvalho Bryl MazelSanchez Filo Silva Laure Garnier Soner Yildiz Joao PPL Bonifacio Chengyue Niu Nathalia Williams Patrice Francois Nicolaus Schwerk Jennifer Schning Julia Carlens Dorothee Viemann Stephanie Hugues Mirco Schmolke |
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Institution: | 1. Department of Microbiology and Molecular Medicine, University of Geneva, Geneva Switzerland ; 2. Department of Pathology and Immunology, University of Geneva, Geneva Switzerland ; 3. Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover Germany ; 4. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover Germany |
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Abstract: | Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro‐inflammatory cytokines. In humans, it depends on caspase 1/4‐activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1‐F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1‐F2‐deficient mutant of a contemporary IAV resulted in higher levels of caspase‐1 activation, cleavage of gasdermin D, and release of LDH and IL‐1β. Mechanistically, PB1‐F2 limits transition of NLRP3 from its auto‐repressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly. |
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Keywords: | influenza A virus NEK7 NLRP3 PB1‐ F2 pyroptosis |
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