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

描述（由申请方提供）：先天免疫应答通过识别病原体相关分子模式提供抵抗入侵病原体的第一道防线。RIG-I样受体（RIG-I like receptor，RLR），RIG-I、MDA 5和LGP 2是病毒RNA的胞质传感器，并且在先天性抗病毒免疫应答中起关键作用。RLR识别5'三磷酸单链RNA或双链RNA，病毒RNA的特征结构。病毒RNA刺激RLR导致I型干扰素和其他细胞因子的诱导，赋予宿主抗病毒活性并激活获得性免疫应答。然而，通过RLR的病毒RNA传感和信号传导的详细机制仍然没有完全理解。目前还不清楚RLR识别的病毒RNA的结构特征以及RLR如何在分子水平上识别病毒RNA。病毒RNA激活RLR的机制在很大程度上仍然是未知的。本论文的主要研究内容包括：1）确定RLR识别RNA的结构特征; 2）阐明RLR识别RNA的结构基础; 3）研究RLR激活RNA的分子机制。这项研究代表了一个强有力的和全面的调查的结构基础，通过生物化学，结构和功能的研究相结合的方法，通过RLRs的病毒RNA传感。这些研究将提供重要的见解病毒RNA传感的分子机制的RLRs。本研究将显著提高我们对RLR介导的抗病毒免疫应答机制的理解，并为开发更有效的疫苗佐剂和新型治疗试剂以调节抗病毒免疫应答提供结构框架。

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.