Regulatory mechanisms of the MDA5-mediated antiviral interferon response

描述(申请人提供)：尽管在全球范围内共同努力控制与病毒相关的疾病，但它们仍然是一个主要的公共卫生问题。宿主对病毒感染的即时反应依赖于模式识别受体(PRRs)，它能感知入侵病毒的核酸或其他保守的结构成分，随后激活信号级联反应，导致干扰素(IFN)介导的抗病毒防御机制。黑色素瘤分化相关基因5(MDA5)是核糖核酸病毒(包括微小核糖核酸病毒和某些黄病毒)的重要胞质受体。与病毒RNA结合后，MDA5的N端caspase招募结构域(CARD)与MAVAS/VISA/IPS-1/CADIF下游伙伴相互作用，触发I型干扰素的产生，以防止病毒生命周期的完成和病毒在体内的传播。尽管最近在破译MDA5信号通路的分子组成方面取得了快速进展，但其抗病毒活性的调节在很大程度上仍然不确定。然而，正是宿主对干扰素产生的调节，决定了病毒感染的结局以及疾病的严重程度和发病机制。因此，这项研究旨在研究胞质病毒RNA受体MDA5的信号转导活性如何受到宿主编码因子的调节，以调节干扰素介导的宿主反应。生化、细胞生物学和结构研究将侧重于详细确定翻译后修饰如何影响MDA5信号转导活性以限制病毒复制(目标1)。本研究将进一步确定调节MDA5抗病毒功能的新宿主细胞因子，并研究它们在MDA5介导的针对RNA病毒感染的免疫监测中的作用(AIM 2)。这项研究不仅将极大地扩展我们对先天性免疫系统调节网络的理解，还将发现在抗病毒天然免疫中发挥关键作用的新的信号分子，从而为病毒感染的治疗干预提供潜在的靶点。

DESCRIPTION (provided by applicant): Despite concerted efforts to control virus-associated diseases worldwide, they still remain a major public health problem. The host's immediate response to viral infections relies on pattern recognition receptors (PRRs) that sense nucleic acids or other conserved structural components of invading viruses and subsequently activate signaling cascades leading to interferon (IFN)- mediated antiviral defense mechanisms. Melanoma differentiation-associated gene 5 (MDA5) has emerged as a key cytosolic receptor for sensing RNA viruses, including picornaviruses and certain Flaviviruses. Upon binding of viral RNA, the N-terminal caspase recruitment domains (CARDs) of MDA5 interact with MAVS/VISA/IPS-1/Cardif downstream partner to trigger type I IFN production to prevent completion of the virus lifecycle as well as virus dissemination in vivo. Despite the recent rapid progress in deciphering molecular components in the MDA5 signaling pathway, the regulation of its antiviral activity remains largely undetermined. However, it is exactly the regulation of the host IFN production, which dictates the outcome of the viral infection as well as severity of disease and pathogenesis. Thus, the proposed study is directed toward investigating how the signal transducing activity of the cytosolic viral RNA receptor MDA5 is regulated by host-encoded factors to modulate IFN-mediated host responses. Biochemical, cell biological and structural studies will focus on defining in mechanistic detail how posttranslational modifications affect the MDA5 signal transducing activity to limit viral replication (Aim 1). This study will further aim at identifying novel host cell factors for regulating MDA5 antiviral function, and at investigating their roles in the MDA5-mediated immune surveillance against RNA virus infections (Aim 2). Insights gained from this study will not only greatly expand our understanding of the regulatory networks of the innate immune system, but also identify novel signaling molecules that play key roles in antiviral innate immunity, thereby providing potential targets for therapeutic intervention against viral infections.