gamma型疱疹病毒诱发B细胞淋巴瘤的机制研究

Human gammaherpesviruses which include Epstein-Barr Virus (EBV) and Kaposi's Sarcoma herpesvirus (KSHV) are tightly associated with B-cell lymphomagenesis. Especially in the setting of immunodeficiency, such as HIV infection, bone marrow or organ transplant patients with immunosuppressive drug treatment, infections with gammaherpesviruses EBV or KSHV greatly increase the incidence of B-cell lymphomas. Due to the restrictive host species of human gammaherpesviruses, there is still no animal model available to study the pathogenesis of associated lymphomas. To understand the mechanism and oncogenesis of gammaherpesviruses in the development of B-cell lymphoma, this study will utilize murine gammaherpesvirus 68 (MHV68) which has been known to be a good candidate for the pathogenesis study of gammaherpesviruses because it shares high homologous genome organization with EBV and KSHV. We have recently developed a breakthrough mouse model, in which MHV68 immortalized fetal liver cells, developed into mature B cells and induced B-cell lymphomas when injected into immunideficient mice. This phenotype recapitulates human gammaherpesvirus-associated lymphomas which majorly occur in immunosuppressed patients. By using this mouse model, we will seek to elucidate the molecular mechanism underlying virus-host interaction of gammaherpesvirus-induced lymphomagenesis and explore the novel therapeutic strategies for gammaherpesvirus-associated lymphomas.

人类γ型疱疹病毒Epstein Barr virus (EBV) 和Kaposi's sarcoma herpesvirus (KSHV)与B细胞淋巴瘤的发生紧密相关。在有免疫缺陷或抑制的人群中， 如HIV感染的病人、骨髓或器官移植的病人， γ型疱疹病毒感染诱发B细胞淋巴瘤的风险尤其大。由于人类γ型疱疹病毒不能感染其他动物，至今还没有一个可以从体内（in vivo）角度来研究人类γ型疱疹病毒体内病理机制的动物模型。为了了解γ型疱疹病毒在B细胞淋巴瘤中的调节作用和致癌机制，本项目将以与人类γ型疱疹病毒有高度同源性的小鼠疱疹病毒murine gammaherpesvirus 68 （MHV68）为模式病毒，并利用我们近期成功创建的通过MHV68转化小鼠胚胎细胞诱发B细胞淋巴瘤的小鼠模型，来研究γ型疱疹病毒在体内诱发B细胞淋巴瘤的分子机制，从而探索γ型疱疹病毒相关淋巴瘤的治疗策略。

Gamma型人类疱疹病毒EBV，KSHV和小鼠模式疱疹病毒MHV68与淋巴瘤的产生和发展紧密相关。我们的研究发现T细胞在调控EBV和MHV68相关的B细胞淋巴瘤中起着关键的作用，进而阐明了T细胞杀伤的效应分子细胞死亡受体CD95介导的细胞凋亡通路是T细胞调控淋巴瘤细胞生长的重要机制。 此外，CD95介导的非细胞凋亡通路被淋巴瘤细胞中MHV68和EBV病毒用于逃逸宿主识别的一种机制，抑制了MHV68和EBV的病毒激活，从而逃逸T细胞的免疫监控。 这项研究对于T细胞免疫治疗EBV相关的淋巴瘤提供了非常重要的理论基础和策略。与此同时， 我们的研究 还揭示了内质网（ER）应急信号调控疱疹病毒潜伏感染和裂解复制中的作用机制。发现了ER应急信号可以抑制潜伏感染的gamma型疱疹病毒的裂解复制；阐明了ER应急信号中诱导的CHOP基因在潜伏感染的gamma型疱疹病毒的裂解复制中是必须的，而且CHOP的表达能通过反馈抑制上游的Bip和ATF4来促进病毒的裂解复制。这项研究为我们治疗EBV相关的B细胞淋巴瘤提供了新方法。