a20 (tnfaip3) deficiency in myeloid cells protects against influenza a virus infectiona20(tnfaip3)髓细胞缺乏预防甲型流感病毒感染.pdfVIP

A20 (Tnfaip3 ) Deficiency in Myeloid Cells Protects against Influenza A Virus Infection Jonathan Maelfait1,2, Kenny Roose2,3, Pieter Bogaert2,4, Mozes Sze1,2, Xavier Saelens2,3, Manolis Pasparakis5, Isabelle Carpentier1,2, Geert van Loo1,2, Rudi Beyaert1,2* 1 Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Ghent, Belgium, 2 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium, 3 Unit of Molecular Virology, Department for Molecular Biomedical Research, Ghent, Belgium, 4 Cell Culture and Sorting Core Facility, Department for Molecular Biomedical Research, Ghent, Belgium, 5 Institute for Genetics, University of Cologne, Cologne, Germany 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-kB 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. Sur