Hepatitis C virus and autophagic response

项目总结 丙型肝炎病毒是一种重要的人类病原体，可导致严重的肝病，包括 急慢性肝炎、肝硬变和肝细胞癌。近年来的研究表明 丙型肝炎病毒在体外和体内均可诱导自噬，以促进其复制。随着自噬的上演 丙型肝炎病毒对这一途径的长期干扰是维持细胞内环境稳定的重要作用 在慢性感染期间可能对丙型肝炎病毒肝病的进展产生深远的影响- 被感染的病人。尽管在过去的几年里，在理解 关于丙型肝炎病毒与自噬之间的关系，许多问题仍然没有答案。这样做的目的是 研究将继续我们之前的研究，以进一步了解丙型肝炎病毒与 自噬。在目标1中，我们将继续我们之前的研究，以探索生物发生的途径 通过确定这些膜小泡的来源并确定丙型肝炎病毒感染细胞中的自噬小体 它们是否来源于吞噬分子的同型融合。正如我们最近的研究表明， 丙型肝炎病毒通过非典型途径诱导自噬，在目标2中，我们将继续描述这一途径。 并研究了丙型肝炎病毒非结构蛋白在诱导这一途径中的作用。此外，作为我们的 初步研究揭示了脂筏与丙型肝炎病毒诱导的自噬小体的特异性关联。 我们还将研究脂筏如何被招募到丙型肝炎病毒诱导的自噬小体中，以及它们可能的情况。 在自噬体膜上介导丙型肝炎病毒RNA复制的作用。我们最近开发了一种 一种从丙型肝炎病毒感染细胞中纯化自噬小体以鉴定其相关基因的新方法 蛋白质因素。在目标3中，我们将继续表征这些蛋白质因子，包括膜联蛋白A2， 载脂蛋白E和突触素7，并确定它们在自噬小体生物发生中的可能作用 和丙型肝炎病毒复制。我们建议的研究将提供重要的信息来理解 丙型肝炎病毒与其宿主细胞之间的相互作用，有助于更好地理解丙型肝炎病毒的生命周期及其 发病机制。这也将为理解细胞自噬途径提供重要信息， 病毒经常利用这一点来增强其复制。

PROJECT SUMMARY Hepatitis C virus (HCV) is an important human pathogen that can cause severe liver diseases including acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Studies in recent years indicated that HCV could induce autophagy both in vitro and in vivo to enhance its replication. As autophagy plays an important role in maintaining cellular homeostasis, the prolonged perturbation of this pathway by HCV during chronic infection can have profound consequences on the progression of liver diseases in HCV- infected patients. Although significant progresses have been made during the past few years to understand the relationship between HCV and autophagy, many questions remain unanswered. The goal of this research is to continue our previous studies to further understand the relationship between HCV and autophagy. In Aim 1, we will continue our previous studies to investigate the biogenesis pathway of autophagosomes in HCV-infected cells by identifying the origin of these membrane vesicles and determine whether they are derived from the homotypic fusion of phagophores. As our recent studies indicated that HCV induced autophagy via a non-canonical pathway, in Aim 2, we will continue to delineate this pathway and examine the roles of HCV nonstructural proteins in the induction of this pathway. In addition, as our preliminary studies revealed the specific association of lipid rafts with autophagosomes induced by HCV, we will also investigate how lipid rafts are recruited to HCV-induced autophagosomes and their possible role in mediating HCV RNA replication on autophagosomal membranes. We have recently developed a novel approach to purify autophagosomes from HCV-infected cells for the identification of their associated protein factors. In Aim 3, we will continue to characterize these protein factors, which include annexin A2, apolipoprotein E and syntaxin 7, and determine their possible roles in the biogenesis of autophagosomes and HCV replication. Our proposed research will provide important information for understanding the interaction between HCV and its host cells and lead to a better understanding of the HCV life cycle and its pathogenesis. It will also provide important information for understanding the cellular autophagic pathway, which is frequently exploited by viruses to enhance their replication.