天然抗病毒免疫是宿主细胞对抗病毒感染的第一道防线。RIG-I和MDA5是细胞质中两种主要的病毒核酸感应蛋白，具有RNA解旋酶活性，并可识别各种病毒RNA及部分DNA，最终激活I型干扰素的产生，以维持细胞的抗病毒状态。RIG-I主要识别带有5'ppp的极短双链RNA（dsRNA）以及不带5'ppp的中等长度（数百碱基对）dsRNA，而MDA5 的配体则为较长的不带5'ppp的dsRNA。我们在2011年发表于Cell Host and Microbe的研究表明，RIG-I对病毒RNA识别需要一种称为PACT的dsRNA结合蛋白的辅助。我们的预实验结果也显示PACT可以激活MDA5诱导的干扰素反应。我们将利用脑心肌炎病毒(EMCV)和轮状病毒作为模型，阐明PACT和MDA5共同识别病毒RNA的原理。本课题将为发展新的抗病毒及免疫调节药物或增强现有疫苗的免疫效果奠定重要的理论基础。

Innate immune response is the first line of defense against viral infection. In the case of RNA virus infection, RIG-I-like receptors (RLRs) such as RIG-I and MDA5 form the major cytoplasmic sensors that recognize viral RNA ligands with defined molecular signatures. Ligated RIG-I or MDA5 activates several signaling complexes and hence induces type I interferon production. Although the underlying mechanism of differential recognition of viral RNA ligands by RIG-I and MDA5 remains obscure, there is a general consensus that RIG-I selectively senses 5' triphosphate-ended short dsRNA while MDA5 recognizes long dsRNA without 5' triphosphate terminus. We are interested in how these RLRs sense the invading viruses and recently published our findings in Cell Host and Microbe, which demonstrated that RIG-I sensing and activation require a host dsRNA binding protein PACT in Sendai virus-infected cells. In our preliminary study we found that PACT also facilitates MDA5-mediated interferon production upon poly (I:C) stimulation. In this project we will use different approaches to investigate the mechanism by which PACT augments MDA5 activation. We will characterize the interaction between PACT and MDA5, determine the influence of PACT on MDA5 activation and derive the molecular mechanisms. Using EMCV and rotavirus as models, we will shed light on PACT-mediated activation of MDA5 in the context of viral RNA recognition. Our work will lead to a new paradigm in the study of innate antiviral immunity and provide a solid foundation for the development of new and better antivirals, immunomodulatory agents and adjuvants.