The Structural Basis of Viral RNA Sensing by the RIG-I Like Receptors

描述(由申请人提供)：先天性免疫反应通过识别病原体相关的分子模式提供了抵御入侵病原体的第一道防线。RIG-I样受体(RIG-I)、MDA5和LGP2是病毒RNA的胞浆感受器，在先天抗病毒免疫反应中发挥关键作用。RLR识别病毒RNA的标志性结构--5‘三磷酸单链或双链RNA。病毒RNA刺激RLR可诱导I型干扰素和其他细胞因子，赋予宿主抗病毒活性，并激活获得性免疫反应。然而，RLRs对病毒RNA的感知和信号传递的详细机制仍不完全清楚。目前还不清楚RLRs识别的病毒RNA的结构特征是什么，以及RLRs是如何在分子水平识别病毒RNA的。病毒RNA激活RLRs的机制在很大程度上仍不清楚。这项研究将集中于阐明RLRs感知病毒RNA的结构基础，具体目的如下：1)确定RLRs识别的RNA的结构特征；2)阐明RLRs识别RNA的结构基础；3)研究RLRs激活RLRs的分子机制。本研究通过生化、结构和功能研究相结合的方法，对RLRs感知病毒RNA的结构基础进行了有力而全面的研究。这些研究将为RLRs感知病毒RNA的分子机制提供重要的见解。这项研究将极大地促进我们对RLRs介导的抗病毒免疫反应机制的理解，并为开发更有效的疫苗佐剂和新型治疗试剂来调节抗病毒免疫反应提供一个结构框架。

DESCRIPTION (provided by applicant): Innate immune responses provide the first line of defense against invading pathogens through the recognition of pathogen associated molecular patterns. The RIG-I like receptors (RLRs), RIG-I, MDA5 and LGP2, are cytosolic sensors of viral RNA and play pivotal roles in innate antiviral immune responses. The RLRs recognize 5' triphosphate single-stranded RNA or double-stranded RNA, signature structures of viral RNA. Stimulation of the RLRs by viral RNA leads to the induction of type I interferons and other cytokines, conferring antiviral activity to the host and activating the acquired immune responses. However, the detailed mechanisms of viral RNA sensing and signaling by the RLRs are still not fully understood. It is not clear what are the structural features of viral RNA recognized by the RLRs and how the RLRs recognize viral RNA at molecular level. The mechanisms of RLRs activation by viral RNA are still largely unknown. The proposed research will focus on elucidating the structural basis of viral RNA sensing by the RLRs with the following specific aims: 1) determine the structural features of RNA recognized by the RLRs; 2) elucidate the structural basis of RNA recognition by the RLRs; 3) investigate the molecular mechanism of RLRs activation by RNA. This research represents a vigorous and comprehensive investigation of the structural basis for viral RNA sensing by the RLRs through a combined approach of biochemical, structural, and functional studies. These studies will provide important insights into the molecular mechanism of viral RNA sensing by the RLRs. This research will significantly advance our understanding about the mechanisms of antiviral immune response mediated by the RLRs and provide a structural framework for the development of more effective adjuvant for vaccines and novel therapeutic reagents to modulate the antiviral immune responses.