The Host Response to Hepatitis C Virus

 描述（由申请方提供）：控制从急性病毒感染转变为慢性病毒感染的病毒/宿主相互作用尚不清楚。丙型肝炎病毒（HCV）是一种慢性感染的模式RNA病毒，是当代的公共卫生问题。这项申请继续我们的重点是定义肝脏先天免疫的分子机制，赋予急性到慢性HCV感染的结果。我们已经证明，视黄酸诱导基因-I（RIG-I）在识别和结合由HCV RNA内的5'三磷酸和聚尿苷/胞嘧啶（pU/UC）基序组成的病原体相关分子模式（PAMP）后启动肝脏先天免疫应答。在急性感染期间，RIG-I对传播/创始者（T/F）病毒基因组的这种识别导致其修饰和活化以结合MAVS相关膜（MAM）上的MAVS衔接蛋白，并发出限制感染的肝脏先天免疫防御的信号。我们的初步研究现在揭示，患者的T/F基因组在其pU/UC基序内表现出显着的变化，并且这种变化赋予RIG-I的差异识别和结合，从而允许逃避非自我识别。此外，我们发现RIG-I的信号传导依赖于RIG-I转位子蛋白复合物的形成，该蛋白复合物促进RIG-I细胞溶质至膜转位以用于MAVS相互作用和MAM上的信号传导。我们的研究现在表明，这些活动是由RIG-I的可逆乙酰化控制的，并且该过程可能通过以下方式控制： HDAC 6蛋白作为先天免疫的RIG-I辅因子。我们表明，HCV通过NS 3/4A病毒蛋白酶靶向MAM以切割MAVS并破坏RIG-I信号传导来逃避肝脏先天免疫，从而促进慢性感染，并且这种作用依赖于MAM上稳定的NS 3/4A-MAVS相互作用。这种相互作用的破坏恢复先天免疫，以防止急性向慢性HCV转化。我们推测RIG-I通路的调节和肝脏先天免疫是控制HCV感染从急性向慢性转变的主要决定因素。因此，我们将进行研究以：1）确定在急性HCV感染期间病原体识别和来自T/F基因组的差异先天免疫信号传导的RIG-I/PAMP相互作用; 2）确定RIG-I乙酰化在易位子组装和功能中的作用; 3）鉴定介导相互作用以控制RIG-I途径的NS 3/4A/MAVS界面。

 DESCRIPTION (provided by applicant): The virus/host interactions that control the transition from acute to chronic virus infection are not well understood. Hepatitis C virus (HCV) is a model RNA virus of chronic infection and is a contemporary public health problem. This application continues our focus on defining the molecular mechanisms of hepatic innate immunity that impart acute to chronic HCV infection outcome. We have shown that retinoic acid inducible gene-I (RIG-I) initiates the hepatic innate immune response upon recognition and binding of the pathogen associated molecular pattern (PAMP) consisting of 5' triphosphate and the poly-uridine/cytosine (pU/UC) motif within the HCV RNA. During acute infection this recognition of the transmission/founder (T/F) viral genome by RIG-I results in its modification and activation to bind the MAVS adaptor protein on mitochondria-associated membranes (MAM) and signal hepatic innate immune defenses that restrict infection. Our preliminary studies now reveal that T/F genomes from patients exhibit remarkable variation within their pU/UC motif, and that this variation imparts differential recognition and binding by RIG-I that allows escape from non-self-recognition. Moreover, we have found that signaling by RIG-I is dependent on formation of a RIG-I translocon protein complex that facilitates RIG-I cytosol-to-membrane translocation for MAVS interaction and signaling on the MAM. Our studies now reveal that these activities are governed by the reversible acteylation of RIG-I, and that this process is likely controlled through the HDAC6 protein as a RIG-I cofactor of innate immunity. We show that HCV evades hepatic innate immunity via MAM targeting by the NS3/4A viral protease to cleave MAVS and disrupt RIG-I signaling, thereby facilitating chronic infection, and this action is dependent on stable NS3/4A- MAVS interaction on the MAM. Disruption of this interaction restores innate immunity to prevent acute to chronic HCV transition. We hypothesize that regulation of the RIG-I pathway and hepatic innate immunity are major determinants controlling the acute to chronic transition of HCV infection. We will therefore conduct studies to: 1) Define the RIG-I/PAMP interactions of pathogen recognition and differential innate immune signaling from T/F genomes during acute HCV infection; 2) Determine the role of RIG-I acetylation in translocon assembly and function; 3) Identify the NS3/4A/MAVS interface that mediates interaction to control the RIG-I pathway.