FUNCTION OF IRF7 IN RESPONSE TO VIRUS INFECTION

IRF7 应对病毒感染的功能

• 批准号: 6374366
• 负责人: David E Levy
• 金额: $ 28.88万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374366
• 关键词: Orthomyxoviridae; biological signal transduction; gene induction /repression; host organism interaction; interferons; laboratory mouse; microorganism immunology; phosphorylation; protein binding; protein localization; protein structure; transcription factor; vaccinia virus; virus infection mechanism

Resistance to viral infection involves activation of the innate immune system. An essential component of this response is activation of an alarm system that signals the presence of an invading pathogen. This system includes induction of inflammatory mediators, such as interleukin 1 and tumor necrosis factor, and antiviral products such as type I interferon (IFN) which in turn activates a cascade of cellular gene products involved in antiviral defense, some of which are also directly induced in response to virus infection. 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 transcriptional mechanisms involved in activation of cellular genes in response to IFN treatment have been recently characterized, the mechanisms responsible for the initial induction of the IFN genes themselves and the signals that set this process in motion following detection of an active viral infection remain unclear. The type I IFN gene family is composed of 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. A shared component that nonetheless is responsible for some aspects of these distinct expression patterns is the transcription factor IFN regulatory factor 7 (IRF7). IRF7 is essential for the expression of IFNalpha6 and modulates the expression of IFNalpha4 while playing only a minor role in induction of IFNbeta. The activity of IRF7 is controlled at the level of protein abundance, subcellular compartmentalization, DNA binding, and transactivation, all of which are altered by viral infection. Its central position in the activation of IFN genes and its direct response to viral infection make it an ideal target to elucidate the signaling pathways initiated by virus and the cellular and transcriptional control mechanisms involved in innate immune gene induction. This proposal will characterize the structural and functional attributes of IRF7 and its cousin IRF3 that contribute to the specificity of IFN gene induction and will delineate mechanisms of virus-induced regulation of IRF7 and the cellular signaling pathway that detects and responds to viral infection. These studies should reveal important features of transcriptional regulatory mechanisms and uncover the nature of the antiviral alarm system.

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激活警报系统，发出入侵病原体存在的信号。 该系统包括诱导炎性介质，如白细胞介素1和肿瘤坏死因子，以及抗病毒产物，如I型干扰素（IFN），其进而激活参与抗病毒防御的细胞基因产物的级联，其中一些也响应于病毒感染而被直接诱导。 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。 虽然最近已经表征了响应于IFN治疗的细胞基因激活中涉及的信号级联和转录机制，但是负责IFN基因本身的初始诱导的机制以及在检测到活性病毒感染后启动该过程的信号仍然不清楚。I型IFN基因家族由十几个基因组成，这些基因分为两个亚家族α和β，其中α亚家族由至少两组组成，这两组在小鼠中表现出不同的表达模式（早期和延迟），表现为IFN α 4（早期）和IFN α 6（晚期）。 虽然所有的IFN基因诱导病毒的反应，机制，动力学和细胞类型特异性的诱导是不同的。 然而，负责这些不同表达模式的某些方面的共享组分是转录因子IFN调节因子7（IRF7）。 IRF7对于IFN α 6的表达是必需的，并且调节IFN α 4的表达，而在IFN β的诱导中仅起次要作用。 IRF7的活性在蛋白质丰度、亚细胞区室化、DNA结合和反式激活的水平上受到控制，所有这些都被病毒感染改变。它在IFN基因激活中的中心地位以及对病毒感染的直接应答使其成为阐明病毒启动的信号通路以及参与先天免疫基因诱导的细胞和转录调控机制的理想靶点。该提案将表征IRF7及其表亲IRF3的结构和功能属性，这些属性有助于IFN基因诱导的特异性，并将描述病毒诱导的IRF7调节机制和检测和响应病毒感染的细胞信号传导途径。 这些研究将揭示转录调控机制的重要特征，并揭示抗病毒警报系统的本质。