FUNCTION OF IRF7 IN RESPONSE TO VIRUS INFECTION

IRF7 应对病毒感染的功能

• 批准号: 6747613
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747613
• 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.

对病毒感染的抗性涉及先天免疫系统的激活。 该响应的一个重要组成部分是激活警报系统，该警报系统信号是入侵病原体的存在。 该系统包括诱导炎症介质（例如白介素1和肿瘤坏死因子）以及诸如I型干扰素（IFN）之类的抗病毒产物，从而激活了一系列涉及抗病毒药防御的细胞基因产物，其中一些也直接引起了对病毒感染的反应。 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。 尽管最近已经表征了涉及细胞基因激活的信号传导级联和转录机制，但已表征了造成IFN基因本身初始诱导的机制，以及在检测到活动病毒感染后将此过程设置为运动的信号尚不清楚。 I型IFN基因家族由十几个基因组成，分为两个亚家族，Alpha和beta，其中α亚家族由至少两组组成，这些组由IFNALPHA4（早期）和IFNALPHA6（早期）和IFNALPHA6（晚期）（晚）（早期）（晚）（晚）表示不同的表达模式（早期和延迟）。 虽然所有IFN基因都响应病毒而诱导，但诱导的机制，动力学和细胞类型的特异性是不同的。 尽管如此，这些不同的表达模式的某些方面的共享组件是转录因子IFN调节因子7（IRF7）。 IRF7对于IFNALPHA6的表达至关重要，并在仅在诱导IFNBETA中扮演较小的作用时调节Ifnalpha4的表达。 IRF7的活性在蛋白质丰度，亚细胞分区化，DNA结合和反式激活的水平下受到控制，所有这些都会因病毒感染而改变。它在IFN基因激活中的中心位置及其对病毒感染的直接反应使其成为阐明病毒引发的信号传导途径以及与先天免疫基因诱导有关的细胞和转录控制机制的理想目标。该建议将表征IRF7及其表弟IRF3的结构和功能属性，这些属性促进了IFN基因诱导的特异性，并将描述病毒诱导的IRF7调控机制以及检测和反应病毒感染的细胞信号传导途径。 这些研究应揭示转录调节机制的重要特征，并揭示抗病毒警报系统的性质。