FUNCTION OF IRF7 IN RESPONSE TO VIRUS INFECTION

对病毒感染的抵抗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。该系统包括诱导炎症介质，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），干扰素反过来激活一系列参与抗病毒防御的细胞基因产物，其中一些也直接被诱导以响应病毒感染。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。虽然信号级联和参与细胞基因响应IFN治疗激活的转录机制最近已被描述，但负责IFN基因本身初始诱导的机制以及在检测到活动性病毒感染后设置这一过程的信号仍不清楚。I型IFN基因家族由十多个基因组成，分为α和β两个亚家族，其中α亚家族由至少两个组组成，在小鼠中以IFNalpha4（早期）和IFNalpha6（晚期）为代表，表现出不同的表达模式（早期和延迟）。虽然所有IFN基因都是针对病毒诱导的，但诱导的机制、动力学和细胞类型特异性是不同的。尽管如此，对这些不同表达模式的某些方面负责的一个共同成分是转录因子IFN调节因子7 （IRF7）。IRF7对IFNalpha6的表达至关重要，并调节IFNalpha4的表达，而在诱导IFNbeta中仅起次要作用。IRF7的活性控制在蛋白丰度、亚细胞区隔化、DNA结合和反激活水平，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及其对病毒感染的直接反应使其成为阐明病毒启动的信号通路以及先天免疫基因诱导中涉及的细胞和转录控制机制的理想靶点。这一建议将描述IRF7及其近亲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调控机制以及检测和响应病毒感染的细胞信号通路。这些研究将揭示转录调控机制的重要特征，揭示抗病毒警报系统的本质。

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.