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.

对病毒感染的抗性涉及先天免疫系统的激活。该反应的一个重要组成部分是诱导1型干扰素（IFN），进而诱导并激活一系列涉及抗病毒防御的细胞基因产物。这些诱导的蛋白激活了能够通过多种机制抑制多种病毒感染的细胞抗病毒态。最近，使用培养细胞对生化的信号传导级联和转录机制对IFN治疗的激活进行了生化，而生化的机制，导致对IFN基因的初始诱导和在体内对IFN反应中的细胞类型特异性差异的初始诱导仍然很大程度上是单的。特别是，虽然很明显，诱导的IFN在限制流感病毒的传播方面起主要作用，但不足以完全防止肺部感染，同时消除其他组织中的感染。 1型IFN基因家族包含十几个基因，分为两个亚家族，Alpha和beta，其中Alpha亚家族由至少两组组成，这些基因由Ifnalpha4（早期）和IFNALPHA6（早期）（晚）（较早）组成，这些基因至少两组显示出不同的表达模式（早期和延迟）。虽然所有IFN基因都是响应病毒诱导的，但诱导的机制，动力学和细胞类型的特异性是独特的，受控的，至少部分由转录因子IFN调节因子3（IRF3）和IRF7。 IRF 7似乎是诱导IFNBETA和IFNALPHA4所必需的，而IRF7对于表达Ifnalpha6是必不可少丰度，亚细胞分区化，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传导级联反应，从而导致抗病毒蛋白诱导。目前未知的I型IFN家族的不同成员是否引起不同的抗病毒活动。该项目将研究以下假设：由于IFN诱导和/或反应受损，肺允许注射流感病毒。 IFN产生和反应细胞的肺部，产生的IFN类型，由病毒和IFN激活的信号传导级联反应以及抗病毒基因产物的诱导将以完全IFN响应性细胞的反应来表征。这些数据将增加我们对为什么流感病毒在肺中有选择地复制的原因，并发现更好地控制病毒感染的潜在策略。