Mordstein Markus, Kochs Georg, Dumoutier Laure, Renauld Jean-Christophe, Paludan Søren R, Klucher Kevin, Staeheli Peter
Department of Virology, University of Freiburg, Freiburg, Germany.
PLoS Pathog. 2008 Sep 12;4(9):e1000151. doi: 10.1371/journal.ppat.1000151.
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.
病毒感染的细胞会分泌多种干扰素（IFN）亚型，这些亚型进而触发抗病毒因子的合成，从而赋予宿主抵抗力。IFN-α、IFN-β和其他I型IFN通过一种普遍表达的共同细胞表面受体进行信号传导，而IFN-λ则使用一种不同的受体复合物进行信号传导，这种受体复合物并非在所有细胞类型中都存在。由于I型IFN受体缺陷小鼠（IFNAR1(0/0)）对各种病毒疾病的易感性大大增加，因此尚不清楚IFN-λ在多大程度上有助于先天免疫。为了解决这个问题，我们对携带流感病毒抗性基因Mx1功能等位基因的小鼠进行了甲型流感病毒感染，因此，与标准实验室小鼠相比，这些小鼠对流感病毒产生了更完整的先天免疫反应。我们证明，鼻内给予IFN-λ可轻易诱导小鼠肺中的抗病毒因子Mx1，并有效保护IFNAR1(0/0)小鼠免受致命性流感病毒感染。相比之下，腹腔注射IFN-λ未能在IFNAR1(0/0)小鼠的肝脏中诱导Mx1，也不能预防嗜肝病毒感染。缺乏功能性IFN-λ受体的小鼠对流感病毒的易感性仅比野生型小鼠略高。然而，同时缺乏IFN-α/β和IFN-λ功能性受体的小鼠则高度敏感，甚至无法限制通常缺乏IFN拮抗因子NS1的非致病性流感病毒突变体。有趣的是，双敲除小鼠对嗜肝病毒的易感性并不比IFNAR1(0/0)小鼠更高。从这些结果我们得出结论，IFN-λ有助于对感染肺部而非肝脏的病毒病原体产生先天抵抗力。
