内质网应激介导疱疹病毒激活潜伏感染EBV的机制研究

Epstein-Barr virus (EBV) infection could cause serious diseases such as nasopharyngeal carcinomas, lymphoma and so on. The reactivation of latent EBV to lytic replication is closely related to its pathogenesis. However, the mechanism underlying EBV reactivation is not yet fully understood. It is clinically evident that many herpesviruses (e.g. HSV) co-infect with EBV, but the effect of this co-infection on EBV reactivation is not clear. We have firstly reported that HSV induced the reactivation of latent EBV by triggering the expression of immediate early gene BZLF1. When it comes to HSV, some research data indicated that HSV infection could induce endoplasmic reticulum stress (ER stress). When it comes to EBV, one study demonstrated that the chemical ER-stress inducer causes the reactivation of latent EBV to lytic replication. Based on these results, we propose a hypothesis that ER stress mediates the latent EBV reactivation induced by herpesvirus co-infection. In this study, we will use herpesvirus co-infection sysytem and the inducers/inhibitors of ER stress to validate this hypothesis. This study will not only find out novel mechanism of latent EBV reactivation but also will be valuable to answer wether ER stress could be serving as a target for therapeutic intervention of EBV associated diseases.

EBV感染可引起鼻咽癌、淋巴瘤等重大疾病，其潜伏周期的激活与其致病机制密切相关，但EBV从潜伏周期进入裂解周期的机制尚不完全清楚。临床大量数据显示HSV等疱疹病毒可以与EBV共感染，但共感染对EBV潜伏激活的影响还不清楚。我们前期研究首次发现，HSV共感染会激活EBV立即早期基因BZLF1的表达，进而激活潜伏感染的EBV（已发表）。对于HSV，一些研究数据提示HSV感染会诱发内质网应激；对于EBV，有研究发现，化学药物诱导内质网应激可以使EBV由潜伏周期进入裂解周期。基于以上背景，我们提出假说：内质网应激介导疱疹病毒激活潜伏感染的EBV。本项目将通过使用疱疹病毒共感染系统及内质网应激的诱导剂和抑制剂等方法，证明这一假说，其意义在于：1）发现疱疹病毒激活潜伏感染EBV的新的分子机制；2）为将内质网应激作为临床干预EBV相关疾病的靶点提供依据。

EBV感染可引起鼻咽癌、淋巴瘤等重大疾病，其潜伏周期的激活与其致病机制密切相关，但EBV从潜伏周期进入裂解周期的机制尚不完全清楚。我们前期研究首次发现，HSV共感染会激活EBV立即早期蛋白ZTA的表达，进而激活潜伏感染的EBV。本项目围绕着疱疹病毒激活潜伏感染EBV的分子机制，从三个层次展开研究，取得以下结论：1)淋巴瘤细胞中，HSV感染通过内质网应激IRE1-XBP1通路激活潜伏感染的EBV；2)鼻咽癌细胞中，RTA介导单纯疱疹病毒激活潜伏感染的EBV；3)通过RNA-Seq发现氧化磷酸化潜在参与HSV感染激活潜伏的EBV。本项目回答了一系列疱疹病毒共感染激活潜伏EBV的基本科学问题，做出了原创性的贡献，也将疱疹病毒共感染激活EBV的研究扩展到动物模型，具有潜在的临床应用。