Deciphering the role of lipid droplets in Hepatitis C virus replication

丙型肝炎病毒感染影响全球约3%的人口，是肝脏相关发病率和死亡率的主要原因之一。丙型肝炎病毒的感染以及病毒的复制与感染的肝细胞的脂质代谢密切相关。在所有慢性感染丙型肝炎病毒的人中，约有一半会患上脂肪肝，这种疾病的特征是感染细胞中的脂滴大量积累。有趣的是，脂滴也成为丙型肝炎病毒感染的关键细胞器，特别是对病毒后代的组装。然而，为什么病毒需要脂滴进行复制，以及丙型肝炎病毒复制后期步骤的机制细节仍未明确。我们的目标是从分子细节上阐明脂滴在丙型肝炎病毒感染和发病机制中的作用。我们以前已经证明，参与脂滴生物发生和功能的宿主蛋白是病毒复制的关键调节因子。然后，我们比较了感染丙型肝炎病毒的细胞和对照细胞中的脂滴相关蛋白，并确定了可能作为宿主依赖或限制因子的候选蛋白，现在将对其进行详细的分子研究。功能注释表明，丙型肝炎病毒感染导致脂滴与代谢功能和/或调节脱节。这里提出的实验将破译丙型肝炎病毒组装、成熟和出口的分子机制和时间/空间协调。此外，他们还将进一步阐明脂滴在丙型肝炎病毒复制和发病机制中的作用。

Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and is one of the leading causes of liver-related morbidity and mortality. HCV infection as well as replication of the virus is closely tied to the lipid metabolism of infected hepatocytes. About half of all individuals chronically infected with HCV develop fatty liver disease, a condition characterized by the massive accumulation of lipid droplets in infected cells. Intriguingly, lipid droplets also emerged as crucial organelles for HCV infection, particularly for assembly of viral progeny. However, why the virus requires lipid droplets for replication as well as the mechanistic details of the late steps of HCV replication remain ill defined. Our goal is to elucidate in molecular detail the role of lipid droplets in HCV infection and pathogenesis. We have previously shown that host proteins involved in lipid droplet biogenesis and function serve as key regulators of viral replication. We then compared lipid droplet-associated proteins in HCV-infected versus control cells and identified candidate proteins that may serve as host-dependency or -restriction factors that will be now studied in molecular detail. Functional annotation suggests that HCV infection causes a disconnection of lipid droplets from metabolic function and/or regulation. The experiments proposed here will decipher molecular mechanisms and temporal/spatial coordination of HCV assembly, maturation, and egress. In addition they will further elucidate the function of lipid droplets in HCV replication and pathogenesis.