Hepatitis C Virus-Induced Liver Pathogenesis

描述（由申请人提供）：丙型肝炎病毒感染最常导致慢性肝炎，约三分之一的患者发展为肝硬化，其中少数发展为肝细胞癌。这种感染还与脂肪肝有关。HCV RNA复制和成熟活动与内质网（ER）膜修饰的膜结构（包括脂滴）改变有关。最近几个实验室的工作表明细胞脂质/脂肪酸合成途径在病毒复制、形态发生和分泌过程中的作用。这些病毒活动诱导内质网应激，表现为未折叠蛋白反应（UPR）。此外，这些活性改变钙稳态并诱导HCV表达细胞的氧化应激。钙信号的结果之一是钙依赖性钙蛋白酶的激活。HCV诱导的UPR对CD1d表达的影响将在响应内质网应激的HCV感染中进行检测。CD1d加工和脂质抗原装载由微粒体甘油三酯转移蛋白（MTP）催化，HCV基因表达调节内质网中MTP的活性。因此，hcv诱导的UPR影响先天免疫。在这项研究中，我们建议研究hcv诱导的内质网应激/UPR反应改变细胞内事件进程的机制。我们进一步建议研究UPR的活化组分在病毒感染过程中的作用。这些研究将为与HCV感染相关的肝脏疾病发病机制提供独特的见解。

DESCRIPTION (provided by applicant): Hepatitis C virus infection most often leads to chronic hepatitis and about one third of patients develop cirrhosis and a minority of those develops hepatocellular carcinoma. The infection is also associated with fatty liver disease. HCV RNA replication and maturation activities are associated with the altered endoplasmic reticular (ER) membranes modified membranous structures including lipid droplets. Recent work from several laboratories indicates role of cellular lipid/fatty acid synthetic pathways in viral replication, morphogenesis and secretion processes. These viral activities induce ER stress, which manifests as an unfolded protein response (UPR). Furthermore, these activities alter calcium homeostasis and induce oxidative stress in HCV expressing cells. One of the consequences of the calcium signaling is the activation of calcium-dependent calpain proteases. The effect of HCV-induced UPR in CD1d expression will be examined in HCV infection in response to ER stress. CD1d processing and lipid antigen loading is catalyzed by microsomal triglyceride transfer protein (MTP) and HCV gene expression regulates MTP activity in the ER. Thus, HCV-induced UPR affects innate immunity. In this study, we propose to investigate the mechanism(s) by which HCV-induced ER stress/UPR response alters the course of intracellular events. We further propose to investigate the role of activated components of the UPR in the viral infectious processes. These studies will provide unique insights into the mechanisms of liver disease pathogenesis associated with HCV infection. PUBLIC HEALTH RELEVANCE: Hepatitis C virus infection is the leading cause of chronic liver disease, and infection can progress to cirrhosis, steatosis, and hepatocellular carcinoma. HCV gene expression induces an ER stress response, which activates a whole host of cellular factors and functions that manifests in liver disease pathogenesis. In this study, we propose to investigate the impact of ER stress response/unfolded protein response in affecting lipid metabolic pathways, cellular proteases, which in turn affect viral functions including replication, morphogenesis/secretion and ultimately in liver disease pathogenesis.