LUNG INTERFERON IN INFLUENZA VIRUS INFECTION

肺干扰素在流感病毒感染中的作用

• 批准号: 6610320
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610320
• 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.

抵抗病毒感染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诱导 1 型干扰素 (IFN)，进而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，能够通过多种机制抑制多种病毒感染。虽然最近使用培养细胞对 IFN 治疗反应中细胞基因激活所涉及的信号级联和转录机制进行了生化表征，但负责 IFN 基因初始诱导的机制以及对 IFN 反应的细胞类型特异性差异对于vivo，人们仍然知之甚少。特别是，虽然很明显诱导性干扰素在限制流感病毒的传播方面发挥着重要作用，但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，分为两个亚家族：α和β，其中α亚家族由至少两组显示不同的表达模式（早期和延迟）组成，在小鼠中以IFNα4（早期和延迟）为代表。 ) 和 IFNα6（晚期）。虽然所有 IFN 基因都是针对病毒而诱导的，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 IFN 调节因子 3 (IRF3) 和 IRF7 控制。 IRF 7似乎是诱导IFNβ和IFNα4所必需的，而IRF7对于IFNα6的表达是必需的，调节IFNα4的表达，并且发挥作用，而IRF7对于IFNα6的表达是必需的，调节IFNα4的表达，并且发挥作用。在 IFNβ、IRF3 和 IRF7 的诱导中仅发挥很小的作用，这些作用是在蛋白质丰度、亚细胞区室化、DNA 结合和反式激活，所有这些都会因病毒感染而改变。产生 IFN 后，靶细胞通过由 JAK 和 STAT 家族成员控制的第二个信号级联反应，从而诱导抗病毒蛋白的产生。目前尚不清楚 I 型干扰素家族的不同成员是否诱导不同的抗病毒活性。该项目将检验以下假设：由于 IFN 诱导和/或反应受损，肺部允许注射流感病毒。肺部的 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表征对完全 IFN 应答细胞的反应。这些数据将加深我们对流感病毒为何在肺部选择性复制的理解，并揭示更好控制病毒感染的潜在策略。