Interferon-λ Contributes to Innate Immunity of Mice against Influenza A Virus but Not against Hepatotropic Viruses

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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-α, IFN-β and other type I IFNs signal through a common universally expressed cell surface receptor, whereas IFN-λ uses a distinct receptor complex for signaling that is not present on all cell types. Since type I IFN receptor-deficient mice (IFNAR10/0) exhibit greatly increased susceptibility to various viral diseases, it remained unclear to which degree IFN-λ 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-λ readily induced the antiviral factor Mx1 in mouse lungs and efficiently protected IFNAR10/0 mice from lethal influenza virus infection. By contrast, intraperitoneal application of IFN-λ failed to induce Mx1 in the liver of IFNAR10/0 mice and did not protect against hepatotropic virus infections. Mice lacking functional IFN-λ receptors were only slightly more susceptible to influenza virus than wild-type mice. However, mice lacking functional receptors for both IFN-α/β and IFN-λ 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 IFNAR10/0 mice. From these results we conclude that IFN-λ contributes to inborn resistance against viral pathogens infecting the lung but not the liver. The contribution of IFN-λ to innate immunity against virus-induced diseases has remained unclear to date as appropriate mouse models were not available. We now present evidence that IFN-λ is involved in the antiviral defense. Mice lacking functional IFN-λ receptors were only slightly more susceptible to influenza virus than wild-type mice, but intranasal administration of IFN-λ efficiently protected IFN-α/β receptor-deficient mice from lethal influenza virus infection and induced the antiviral factor Mx1 in lungs. Mice lacking functional receptors for both IFN-α/β and IFN-λ were hypersensitive and failed to restrict even usually non-pathogenic influenza virus mutants lacking the IFN-antagonistic factor NS1. By contrast, intraperitoneal application of IFN-λ failed to induce Mx1 in the liver of mice and did not protect against hepatotropic viruses. Furthermore, double-knockout mice were not more susceptible against hepatotropic viruses than IFN-α/β receptor-deficient mice, indicating that IFN-λ contributes to resistance against viral pathogens infecting the lung but not the liver.