FUNCTION OF IRF7 IN RESPONSE TO VIRUS INFECTION

对病毒感染的抵抗涉及到天然免疫系统的激活。这一反应的一个基本组成部分是激活警报系统，发出入侵病原体存在的信号。这个系统包括诱导炎症介质，如白介素1和肿瘤坏死因子，以及抗病毒产品，如I型干扰素(干扰素)，它反过来激活参与抗病毒防御的一系列细胞基因产物，其中一些也是在病毒感染时直接诱导的。这些诱导蛋白激活细胞抗病毒状态，能够通过各种机制抑制不同的病毒感染。虽然最近已经确定了干扰素治疗后细胞基因激活所涉及的信号级联和转录机制，但最初诱导干扰素基因本身的机制以及在检测到活跃的病毒感染后启动这一过程的信号仍不清楚。I型干扰素基因家族由十几个基因组成，分为α和β两个亚家族，其中阿尔法亚家族至少由两组组成，在小鼠中表现出不同的表达模式(早期和延迟)，表现为IFNalpha4(早期)和IFNalpha6(晚期)。虽然所有的干扰素基因都是对病毒的应答而诱导的，但诱导的机制、动力学和细胞类型特异性是不同的。一个共同的成分，但负责这些不同的表达模式的某些方面是转录因子干扰素调节因子7(IRF7)。IRF7对IFNalpha6的表达是必不可少的，并调节IFNalpha4的表达，而在诱导IFNbeta的过程中只起到很小的作用。IRF7的活性被控制在蛋白质丰度、亚细胞区隔、DNA结合和反式激活的水平上，所有这些都会因病毒感染而改变。它在干扰素基因激活中的中心位置和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参与先天性免疫基因诱导的细胞和转录调控机制的理想靶点。这项建议将描述IRF7及其近亲IRF3的结构和功能属性，这些属性有助于干扰素基因诱导的特异性，并将描述病毒诱导调节IRF7的机制以及检测和响应病毒感染的细胞信号通路。这些研究应该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。

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.