LUNG INTERFERON IN INFLUENZA VIRUS INFECTION

肺干扰素在流感病毒感染中的作用

• 批准号: 6480396
• 负责人: David E Levy
• 金额: $ 14.98万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6480396
• 关键词: Orthomyxoviridae; biological signal transduction; fibroblasts; genetically modified animals; host organism interaction; influenzavirus A; interferons; laboratory mouse; lung; microorganism immunology; protein biosynthesis; respiratory epithelium; respiratory infections; transcription factor; virus replication

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.

对病毒感染的抵抗力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，这反过来又诱导和激活参与抗病毒防御的细胞基因产物级联。这些诱导的蛋白质激活细胞的抗病毒状态，能够通过多种机制抑制各种病毒感染。虽然最近已经使用培养的细胞进行生化表征了响应于IFN处理的细胞基因活化中涉及的信号级联和转录机制，但是负责IFN基因的初始诱导和体内响应于IFN的细胞类型特异性差异的机制仍然在很大程度上未知。特别是，虽然很明显诱导的IFN在限制流感病毒的传播中起主要作用，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基因家族包含十几个基因，分为两个亚家族，α和β，α亚家族由至少两组组成，在小鼠中表现为IFN α 4（早期）和IFN α 6（晚期）的不同表达模式（早期和延迟）。虽然所有IFN基因都是响应于病毒而被诱导的，但诱导的机制、动力学和细胞类型特异性是不同的，至少部分地由转录因子IFN调节因子3（IRF 3）和IRF 7控制。IRF 7似乎是诱导IFN β和IFN α 4所必需的，而IRF 7是IFN α 6表达所必需的，调节IFN α 4的表达，并且在IFN β的诱导中仅起次要作用，IRF 3和IRF 7在蛋白质丰度、亚细胞区室化、DNA结合和反式激活，所有这些都被病毒感染改变。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。I型IFN家族的不同成员是否诱导不同的抗病毒活性目前尚不清楚。本项目将检验由于干扰素诱导和/或应答受损而导致肺允许流感病毒注射的假设。肺的IFN产生和应答细胞、产生的IFN类型、由病毒和IFN激活的信号级联以及抗病毒基因产物的诱导将在对完全IFN应答细胞的应答中表征。这些数据将增加我们对流感病毒在肺部选择性复制的理解，并揭示更好地控制病毒感染的潜在策略。