Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses.
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.
Mordstein
Markus
M
Department of Virology, University of Freiburg, Freiburg, Germany.
Kochs
Georg
G
Dumoutier
Laure
L
Renauld
Jean-Christophe
JC
Paludan
Søren R
SR
Klucher
Kevin
K
Staeheli
Peter
P
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
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
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