Mechanisms of Reactivation of Epstein-Barr Virus from Latency to Lytic Replicatio

EB病毒(Epstein-Barr Virus，EBV)是一种普遍存在的人类疱疹病毒，可感染B淋巴细胞和 上皮细胞。根据细胞类型及其分化状态的不同，感染EBV会导致 细胞死亡或潜伏感染的裂解复制。潜伏的EBV感染与几种B细胞有关 和上皮细胞恶性肿瘤，包括Burkitt淋巴瘤、霍奇金病、非霍奇金淋巴瘤 在免疫功能低下的个体中，鼻咽癌和一些胃癌。因此， 了解EBV潜伏期相对于裂解复制的调节对于开发治疗方法至关重要 这些疾病。EB病毒BZLF1和BRLF1基因编码裂解所必需的多功能蛋白 复制。虽然BZLF1和BRLF1启动子在潜伏感染的细胞中不活跃，但细胞分化 某些细胞信号通路的激活物可以诱导BZLF1和BRLF1的表达，促进EBV 重新激活为裂解复制。在这个项目中，我们将(I)确定在以下方面起关键作用的细胞因子 调节这两个即刻早期基因在B细胞和上皮细胞中的表达，以及(Ii) 研究这些因素如何有助于控制潜伏期和裂解性EBV感染之间的平衡 细胞类型的多样性和细胞分化的过程中。结合项目5，这些成果可能会导致 到治疗EBV相关癌症的新疗法。

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus virus that can infect both B lymphocytes and epithelial cells. Depending upon the cell type and its state of differentiation, infection by EBV leads to either lytic replication with cell death or a latent infection. Latent EBV infections are associated with several B-cell and epithelial-cell malignancies including Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas in immunocompromised individuals, nasopharyngeal carcinoma, and some gastric carcinomas. Thus, understanding regulation of EBV latency versus lytic replication is crucial for developing therapies to treat these diseases. The BZLF1 and BRLF1 genes of EBV encode multifunctional proteins essential for lytic replication. While the BZLF1 and BRLF1 promoters are inactive in latently infected cells, cell differentiation and activators of certain cell signaling pathways can induce BZLF1 and BRLF1 expression, promoting EBV reactivation into lytic replication. In this Project, we will (i) identify cellular factors that play key roles in regulating expression of these two immediate-early genes in both B cells and epithelial cells, and (ii) examine how these factors contribute to controlling the balance between latent and lytic EBV infection in a variety of cell types and during cellular differentiation. In conjunction with Project 5, these results may lead to new therapies for treating EBV-associated cancers.