title: A20 (Tnfaip3) deficiency in myeloid cells protects against influenza A virus infection.
abstract: The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections.
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, VIB, Ghent, Belgium [corrected].
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maelfait
authors.forename: Kenny
authors.initials: K
authors.lastname: Roose
authors.forename: Pieter
authors.initials: P
authors.lastname: Bogaert
authors.forename: Mozes
authors.initials: M
authors.lastname: Sze
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carpentier
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral; D009980:Influenza A virus / Q000472:pathogenicity* / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000821:virology; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; C494233:Irf3 protein, mouse; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse