REGULATORY MECHANISMS OF THE MDA5-MEDIATED ANTIVIRAL INTERFERON RESPONSE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 先天免疫的一个关键组成部分是产生I型干扰素(IFN)，这是一种旨在限制病毒复制和体内病毒传播的细胞因子家族。为了诱导抗病毒干扰素反应，哺乳动物宿主进化出了各种模式识别受体(PRRs)，这些受体可以检测病毒病原体的核酸或其他保守的结构成分，然后启动信号级联反应，从而诱导干扰素的诱导。黑色素瘤分化相关基因5(MDA5)是检测微小核糖核酸病毒和某些黄病毒等多种RNA病毒的重要细胞质传感器。此外，最近的研究表明，MDA5在宿主体内对副粘病毒的先天免疫反应中也是至关重要的。对免疫信号通路的严格调控是成功应对病毒感染的免疫反应的关键。当病毒感染时，正向调控机制导致干扰素信号的快速激活，而负向调控机制则需要防止不需要的或过量的干扰素的产生。因此，这项拟议的研究的目标是更好地了解先天性免疫中的调节网络，特别是病毒RNA传感器MDA5。总体假设是，MDA5的抗病毒活性受细胞蛋白和病毒编码因子调节，以逃避病毒免疫。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A key component of innate immunity is the production of type I interferons (IFNs), a family of cytokines designed to limit viral replication as well as virus dissemination in vivo. To elicit antiviral IFN responses, mammalian hosts have evolved a variety of pattern recognition receptors (PRRs), that detect nucleic acids or other conserved structural components of viral pathogens and subsequently initiate signaling cascades leading to IFN induction. Melanoma differentiation-associated gene 5 (MDA5) has emerged as a key cytosolic sensor for the detection of various RNA viruses, including picornaviruses and certain Flaviviruses. In addition, it has been recently shown that MDA5 is also critical for the host innate immune response to paramyxoviruses in vivo. Tight regulation of immune signaling pathways is essential for a successful immune response to viral infections. Whereas positive regulatory mechanisms lead to the rapid activation of IFN signaling upon viral infection, negative regulatory mechanisms are required to prevent unwanted or excessive IFN production. Thus, the goal of the proposed study is to better understand the regulatory networks in innate immunity with a specific focus on the viral RNA sensor MDA5. The overall hypothesis is that MDA5 antiviral activity is regulated by cellular proteins as well as by virus-encoded factors for viral immune evasion.