title: Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses.
abstract: Virus-infected cells secrete a broad range of interferon (IFN) subtypes which in turn trigger the synthesis of antiviral factors that confer host resistance. IFN-alpha, IFN-beta and other type I IFNs signal through a common universally expressed cell surface receptor, whereas IFN-lambda uses a distinct receptor complex for signaling that is not present on all cell types. Since type I IFN receptor-deficient mice (IFNAR1(0/0)) exhibit greatly increased susceptibility to various viral diseases, it remained unclear to which degree IFN-lambda might contribute to innate immunity. To address this issue we performed influenza A virus infections of mice which carry functional alleles of the influenza virus resistance gene Mx1 and which, therefore, develop a more complete innate immune response to influenza viruses than standard laboratory mice. We demonstrate that intranasal administration of IFN-lambda readily induced the antiviral factor Mx1 in mouse lungs and efficiently protected IFNAR1(0/0) mice from lethal influenza virus infection. By contrast, intraperitoneal application of IFN-lambda failed to induce Mx1 in the liver of IFNAR1(0/0) mice and did not protect against hepatotropic virus infections. Mice lacking functional IFN-lambda receptors were only slightly more susceptible to influenza virus than wild-type mice. However, mice lacking functional receptors for both IFN-alpha/beta and IFN-lambda were hypersensitive and even failed to restrict usually non-pathogenic influenza virus mutants lacking the IFN-antagonistic factor NS1. Interestingly, the double-knockout mice were not more susceptible against hepatotropic viruses than IFNAR1(0/0) mice. From these results we conclude that IFN-lambda contributes to inborn resistance against viral pathogens infecting the lung but not the liver.
authors.affiliation: Department of Virology, University of Freiburg, Freiburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Mordstein
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.forename: Laure
authors.initials: L
authors.lastname: Dumoutier
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.forename: Kevin
authors.initials: K
authors.lastname: Klucher
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000276:immunology; D006507:Hepatovirus / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D009980:Influenza A virus / Q000276:immunology*; D008168:Lung / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D064547:Myxovirus Resistance Proteins; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D017471:Receptors, Interferon / Q000172:deficiency / Q000276:immunology; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D016207:Cytokines; D019204:GTP-Binding Proteins; D064547:Myxovirus Resistance Proteins; D017471:Receptors, Interferon; C579070:Mx1 protein, mouse; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda
references.citation: J Immunol. 2005 Jun 1;174(11):7234-41
references.pmid: 15905569
references.citation: J Virol. 2003 Feb;77(4):2747-52
references.pmid: 12552016
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Nov;289(5):G960-8
references.pmid: 16051921
references.citation: J Gen Virol. 2007 May;88(Pt 5):1403-1409
references.pmid: 17412966
references.citation: Proc Natl Acad Sci U S A. 1983 Apr;80(7):1910-4
references.pmid: 6188159
references.citation: J Immunol. 2008 Feb 15;180(4):2474-85
references.pmid: 18250457
references.citation: Virology. 1998 Dec 20;252(2):324-30
references.pmid: 9878611
references.citation: J Clin Invest. 2002 May;109(10):1271-7
references.pmid: 12021240
references.citation: J Virol. 2007 Feb;81(4):2025-30
references.pmid: 17151098
references.citation: J Gen Virol. 2005 Jun;86(Pt 6):1589-1596
references.pmid: 15914836
references.citation: Nat Immunol. 2003 Jan;4(1):69-77
references.pmid: 12483210
references.citation: J Virol. 2006 May;80(10):5032-40
references.pmid: 16641294
references.citation: J Virol. 2004 Aug;78(15):8219-28
references.pmid: 15254193
references.citation: J Biol Chem. 2004 Jul 30;279(31):32269-74
references.pmid: 15166220
references.citation: J Biol Chem. 2007 May 25;282(21):15319-23
references.pmid: 17395581
references.citation: J Gen Virol. 1987 Mar;68 ( Pt 3):945-8
references.pmid: 3029315
references.citation: J Virol. 2005 Mar;79(6):3851-4
references.pmid: 15731279
references.citation: Cancer Res. 2006 Apr 15;66(8):4468-77
references.pmid: 16618774
references.citation: Immunol Rev. 2004 Dec;202:8-32
references.pmid: 15546383
references.citation: J Virol. 2007 Oct;81(19):10818-21
references.pmid: 17652381
references.citation: J Virol. 2007 Jul;81(14):7749-58
references.pmid: 17507495
references.citation: J Biol Chem. 2007 May 25;282(21):15315-8
references.pmid: 17395582
references.citation: Mol Cell Biol. 1988 Oct;8(10):4518-23
references.pmid: 2903437
references.citation: Nature. 2007 Jul 26;448(7152):501-5
references.pmid: 17618271
references.citation: Eur J Immunol. 2004 Mar;34(3):796-805
references.pmid: 14991609
references.citation: J Interferon Cytokine Res. 2006 Jun;26(6):373-9
references.pmid: 16734557
references.citation: J Biol Chem. 1995 Sep 15;270(37):21606-11
references.pmid: 7665574
references.citation: J Virol. 1995 Apr;69(4):2596-601
references.pmid: 7884909
references.citation: PLoS Pathog. 2008 Mar 14;4(3):e1000017
references.pmid: 18369468
references.citation: EMBO J. 1998 Nov 16;17(22):6660-9
references.pmid: 9822609
references.citation: J Virol. 2001 Feb;75(3):1371-7
references.pmid: 11152510
references.citation: FEBS Lett. 1999 Dec 10;463(1-2):24-8
references.pmid: 10601631
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: Nat Immunol. 2003 Jan;4(1):63-8
references.pmid: 12469119