title: A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection.
abstract: A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20AEC-KO mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20AEC-KO mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20AEC-KO mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20AEC-KO mice during later stages of infection. When A20AEC-KO mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20AEC-KO mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection.
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maelfait
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Medical Biotechnology Center, VIB, Ghent, Belgium.
authors.forename: Kenny
authors.initials: K
authors.lastname: Roose
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lars
authors.initials: L
authors.lastname: Vereecke
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Conor
authors.initials: C
authors.lastname: Mc Guire
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Mozes
authors.initials: M
authors.lastname: Sze
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Schuijs
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
authors.forename: Monique
authors.initials: M
authors.lastname: Willart
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Medical Biotechnology Center, VIB, Ghent, Belgium.
authors.forename: Lorena Itati
authors.initials: LI
authors.lastname: Ibañez
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
authors.forename: Hamida
authors.initials: H
authors.lastname: Hammad
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Medical Biotechnology Center, VIB, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology; D015151:Immunoblotting; D007150:Immunohistochemistry; D009980:Influenza A virus; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D016133:Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
references.citation: Curr Opin Virol. 2013 Aug;3(4):425-9
references.pmid: 23721865
references.citation: Nature. 2001 Oct 18;413(6857):732-8
references.pmid: 11607032
references.citation: Nat Rev Immunol. 2014 May;14(5):315-28
references.pmid: 24762827
references.citation: Nature. 2014 Aug 7;512(7512):69-73
references.pmid: 25043000
references.citation: J Gen Virol. 2014 Sep;95(Pt 9):1870-9
references.pmid: 24878639
references.citation: J Exp Med. 2014 Aug 25;211(9):1707-14
references.pmid: 25135297
references.citation: Trends Immunol. 2014 Oct;35(10):483-94
references.pmid: 25182198
references.citation: Curr Opin Virol. 2015 Jun;12:1-6
references.pmid: 25638592
references.citation: Science. 2015 Sep 4;349(6252):1106-10
references.pmid: 26339029
references.citation: J Immunol. 2008 Feb 15;180(4):2562-72
references.pmid: 18250467
references.citation: J Exp Med. 2008 Feb 18;205(2):451-64
references.pmid: 18268035
references.citation: J Exp Med. 2008 Jul 7;205(7):1601-10
references.pmid: 18591409
references.citation: Am J Respir Cell Mol Biol. 2009 Jan;40(1):1-3
references.pmid: 19075182
references.citation: J Exp Med. 2008 Dec 22;205(13):3065-77
references.pmid: 19064696
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3455-60
references.pmid: 19218453
references.citation: Nat Med. 2009 Mar;15(3):277-84
references.pmid: 19234462
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5306-11
references.pmid: 19279209
references.citation: Science. 2000 Sep 29;289(5488):2350-4
references.pmid: 11009421
references.citation: Eur Respir J. 2010 Oct;36(4):722-7
references.pmid: 20223917
references.citation: J Exp Med. 2001 Dec 17;194(12):1835-46
references.pmid: 11748284
references.citation: Am J Respir Crit Care Med. 2002 Aug 1;166(3):268-73
references.pmid: 12153956
references.citation: Science. 2004 Mar 5;303(5663):1529-31
references.pmid: 14976261
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5598-603
references.pmid: 15034168
references.citation: Am J Respir Cell Mol Biol. 2004 Sep;31(3):330-6
references.pmid: 15142865
references.citation: Environ Health Perspect. 1990 Apr;85:51-64
references.pmid: 2200669
references.citation: J Immunol. 1994 Sep 1;153(5):2052-63
references.pmid: 8051410
references.citation: J Immunol. 1998 Oct 1;161(7):3719-28
references.pmid: 9759897
references.citation: J Clin Invest. 1998 Nov 1;102(9):1653-61
references.pmid: 9802879
references.citation: J Biol Chem. 2005 Feb 18;280(7):5571-80
references.pmid: 15579900
references.citation: Am J Respir Cell Mol Biol. 2005 Nov;33(5):455-62
references.pmid: 16055670
references.citation: PLoS Pathog. 2006 Jun;2(6):e53
references.pmid: 16789835
references.citation: J Immunol. 2006 Aug 1;177(3):1817-24
references.pmid: 16849492
references.citation: J Immunol. 2007 Mar 15;178(6):3368-72
references.pmid: 17339430
references.citation: Nat Rev Immunol. 2008 Feb;8(2):142-52
references.pmid: 18204469
references.citation: Clin Microbiol Rev. 2011 Jan;24(1):210-29
references.pmid: 21233513
references.citation: J Exp Med. 2011 Jan 17;208(1):167-80
references.pmid: 21187318
references.citation: Microbes Infect. 2011 Mar;13(3):209-15
references.pmid: 21111841
references.citation: Viral Immunol. 2011 Apr;24(2):77-88
references.pmid: 21449718
references.citation: Science. 2012 Feb 24;335(6071):936-41
references.pmid: 22363001
references.citation: J Leukoc Biol. 2012 Mar;91(3):357-68
references.pmid: 22003207
references.citation: PLoS Pathog. 2012;8(3):e1002570
references.pmid: 22396652
references.citation: Nat Rev Immunol. 2012 Nov;12(11):774-85
references.pmid: 23059429
references.citation: PLoS One. 2013;8(3):e59081
references.pmid: 23527091
references.citation: Mucosal Immunol. 2013 May;6(3):464-73
references.pmid: 23549447
references.citation: J Virol. 2013 Jun;87(12):6925-30
references.pmid: 23576514
references.citation: Nature. 2013 Jul 25;499(7459):500-3
references.pmid: 23823727
references.citation: Curr Opin Virol. 2013 Aug;3(4):430-7
references.pmid: 23721864
references.citation: Immunity. 2009 Apr 17;30(4):556-65
references.pmid: 19362020
references.citation: Immunity. 2009 Apr 17;30(4):566-75
references.pmid: 19362023
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):525-34
references.pmid: 19497281
references.citation: PLoS Pathog. 2009 Oct;5(10):e1000604
references.pmid: 19798428
references.citation: Cell. 2010 Feb 5;140(3):397-408
references.pmid: 20144762
references.citation: J Exp Med. 2010 Mar 15;207(3):521-34
references.pmid: 20212069
references.citation: Nat Immunol. 2010 May;11(5):404-10
references.pmid: 20383149
references.citation: J Biol Chem. 2010 May 14;285(20):14999-5009
references.pmid: 20304918
references.citation: Am J Respir Cell Mol Biol. 2010 Jun;42(6):732-43
references.pmid: 19617401
references.citation: J Exp Med. 2010 Jul 5;207(7):1513-23
references.pmid: 20530205
references.citation: Nat Immunol. 2010 Aug;11(8):656-65
references.pmid: 20644571
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16303-8
references.pmid: 20805493
references.citation: Trends Immunol. 2014 Jan;35(1):22-31
references.pmid: 24246475