LUNG INTERFERON IN INFLUENZA VIRUS INFECTION

对病毒感染的抵抗涉及到天然免疫系统的激活。这种反应的一个重要组成部分是诱导1型干扰素(IFN)，而干扰素反过来又诱导并激活参与抗病毒防御的一系列细胞基因产物。这些诱导蛋白激活细胞抗病毒状态，能够通过各种机制抑制不同的病毒感染。虽然最近利用培养细胞对干扰素处理的反应中涉及细胞基因激活的信号级联和转录机制进行了生化表征，但在体内最初诱导干扰素基因的机制和不同细胞类型对干扰素的反应差异仍然很大程度上是未知的。特别是，虽然很明显，诱导的干扰素在限制流感病毒传播方面发挥了主要作用，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型干扰素基因家族包含十几个基因，分为两个亚家族，α亚家族和β亚家族，其中阿尔法亚家族至少由两组组成，在小鼠中表现出不同的表达模式(早期和延迟)，表现为IFNalpha4(早期)和IFNalpha6(晚期)。虽然所有的干扰素基因都是由病毒诱导的，但诱导的机制、动力学和细胞类型特异性是不同的，至少部分受转录因子干扰素调节因子3(IRF3)和IRF7控制。IRF7似乎是诱导IFNβ和IFNalpha4所必需的，而IRF7对IFNalpha6的表达是必不可少的，调节IFNalpha4的表达并发挥作用，而IRF7对于IFNalpha6的表达是必不可少的，调节IFNalpha4的表达，在诱导IFNbeta的过程中只起到很小的作用，IRF3和IRF7被控制在蛋白质丰度、亚细胞区划、DNA结合和反式激活的水平上，所有这些都被病毒感染改变。在产生干扰素后，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。目前尚不清楚I型干扰素家族的不同成员是否具有不同的抗病毒活性。该项目将检验这样一种假设，即由于干扰素诱导和/或反应受损，肺对流感病毒注射是允许的。肺的干扰素产生和反应细胞、产生的干扰素的类型、病毒和干扰素激活的信号级联以及抗病毒基因产物的诱导将被描述为对完全干扰素反应细胞的反应。这些数据将增加我们对为什么流感病毒在肺部选择性复制的理解，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.