LUNG INTERFERON IN INFLUENZA VIRUS INFECTION

对病毒感染的抵抗涉及先天免疫系统的激活。这种反应的一个重要组成部分是1型干扰素（IFN）的诱导，IFN反过来诱导并激活一系列参与抗病毒防御的细胞基因产物。这些诱导蛋白激活细胞抗病毒状态，能够通过多种机制抑制多种病毒感染。虽然信号级联和转录机制参与了细胞基因对IFN治疗的激活，最近已经用培养细胞进行了生化表征，但IFN基因的初始诱导机制和体内对IFN反应的细胞类型特异性差异在很大程度上仍然未知。特别是，虽然很明显，诱导干扰素在限制流感病毒的传播方面起着主要作用，但它不足以完全预防肺部感染，同时消除其他组织的感染。1型IFN基因家族包含十多个基因，分为α和β两个亚家族，α亚家族由至少两个组组成，在小鼠中以IFNalpha4（早期）和IFNalpha6（晚期）为代表，表现出不同的表达模式（早期和延迟）。虽然所有的IFN基因都是针对病毒诱导的，但诱导的机制、动力学和细胞类型特异性是不同的，至少部分是由转录因子IFN调节因子3 （IRF3）和IRF7控制的。IRF7似乎是诱导IFNbeta和IFNalpha4所必需的，而IRF7是IFNalpha6表达所必需的，调节IFNalpha4的表达，并在诱导IFNbeta中发挥作用，而IRF7是IFNalpha6表达所必需的，调节IFNalpha4的表达，在诱导IFNbeta中仅起次要作用，IRF3和IRF7在蛋白丰度、亚细胞区隔化、DNA结合和反活化水平上受到控制。所有这些都被病毒感染改变了。IFN产生后，靶细胞通过JAK和STAT家族成员控制的第二个信号级联反应，导致抗病毒蛋白的诱导。是否I型IFN家族的不同成员诱导不同的抗病毒活性目前尚不清楚。该项目将检验由于IFN诱导和/或反应受损，肺部允许流感病毒注射的假设。肺中产生IFN和应答的细胞，产生IFN的类型，病毒和IFN激活的信号级联，以及抗病毒基因产物的诱导，将在对IFN完全应答的细胞的反应中被表征。这些数据将增加我们对流感病毒在肺部选择性复制的原因的理解，并揭示更好地控制病毒感染的潜在策略。

Resistance to viral infection involves activation of the innate immune system. An essential component of this response is induction of type 1 interferon (IFN) which in turn induces and activates a cascade of cellular gene products involved in antiviral defense. These induced proteins activate a cellular antiviral state capable of inhibiting diverse viral infections through a wide variety of mechanisms. While the signaling cascade and transcription mechanisms involved in activation of cellular genes in response to IFN treatment have been recently characterized biochemically using cultured cells, the mechanisms responsible for the initial induction of the IFN genes and cell type-specific differences in the response to IFN in vivo are still largely unknown. In particular, while it is clear that induced IFN plays a major role in restricting the spread of influenza virus, it is insufficient to completely prevent infection in the lung while eliminating infection in other tissues. The type 1 IFN gene family contains more than a dozen genes that are divided into two subfamilies, alpha and beta, with the alpha subfamily consisting of at least two groups displaying distinct expression patterns (early and delayed) represented in the mouse by IFNalpha4 (early) and IFNalpha6 (late). While all IFN genes are induced in response to virus, the mechanisms, kinetics, and cell-type specificity of induction are distinct, controlled, at least in part by the transcription factors IFN regulatory factor 3 (IRF3) and IRF7. IRF 7 appears to be required for induction of IFNbeta and IFNalpha4, while IRF7 is essential for the expression of IFNalpha6, modulates the expression of IFNalpha4, and plays, while IRF7 is essential for the expression of IFNalpha6, modulates the expression of IFNalpha4, and plays only a minor role in induction of IFNbeta, IRF3 and IRF7 are controlled at the level of protein abundance, subcellular compartmentalization, DNA binding, and transactivation, all of which are altered by viral infection. Following production of IFN, target cells respond through a second signaling cascade controlled by members of the JAK and STAT families, resulting in induction of antiviral proteins. Whether the different members of the type I IFN family induce distinct antiviral activities is currently unknown. This project will examine the hypothesis that lung is permissive to influenza virus injection due to impaired IFN induction and/or response. The IFN producing and responding cells of the lung, the types of IFN produced, the signaling cascade activated by virus and by IFN, and the induction of antiviral gene products will be characterized in response to fully IFN-responsive cells. These data will increase our understanding of why influenza virus replicates selectively in lung and uncover potential strategies for better controlling viral infection.