Defining the role of plasma cells in the establishment of KSHV infection in human tonsil

摘要/项目摘要 卡波济肉瘤相关疱疹病毒（Kaposi sarcoma-associated herpesvirus，KSHV）是一种致癌的人类疱疹病毒， 肉瘤（KS）以及B细胞淋巴增生性疾病。KSHV- 相关肿瘤是移植患者和HIV感染者发病和死亡的重要原因， 疾病口腔是KSHV生物学的重要部位，因为唾液被认为是KSHV感染的主要方式。 人与人之间的传播扁桃体和其他口腔淋巴组织代表了一种逻辑的 因为它们与唾液接触并且富含用于早期感染事件的靶细胞类型， KSHV感染包括内皮细胞和B淋巴细胞。尽管如此，人类扁桃体中KSHV的生物学 仍然知之甚少。我们已经建立了一个广泛的人类扁桃体标本库， 扁桃体来源的淋巴细胞中的体内感染模型KSHV。利用这些工具，我们最近发现， 成熟浆细胞在KSHV感染的早期是高度靶向的，并且KSHV感染的浆细胞显示出 潜伏性和溶解性感染循环的混合。目前的建议将测试几个假设：（1）浆细胞感染 用作对扁桃体淋巴细胞中感染的总体建立重要的扩增步骤， (2)KSHV编码的细胞因子vIL-6对于通过操纵在淋巴细胞中建立KSHV感染是关键的 和（3）T细胞衍生的细胞因子IL-21支持KSHV传播， vIL-6可促进浆细胞分化，并可部分替代vIL-6在感染早期的作用。的结果 研究将提供关键的机制细节，这将提高我们对KSHV早期事件的理解 传播和建立KSHV感染的淋巴细胞隔室。

Abstract/Project Summary Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic human herpesvirus, which causes Kaposi sarcoma (KS) as well as B cell lymphoproliferative disorders in the absence of adequate immune control. KSHV- associated tumors are a significant cause of morbidity and mortality in transplant patients and individuals with HIV- disease. The oral cavity is an important site for KSHV biology because saliva is believed to be the primary mode of person-to-person transmission for the virus. The tonsil and other oral lymphoid tissues represent a logical anatomical site for early infection events because they are in contact with saliva and are rich in target cell types for KSHV infection including endothelial cells and B lymphocytes. Despite this, the biology of KSHV in the human tonsil remains poorly understood. We have developed an extensive library of human tonsil specimens and a robust ex vivo infection model KSHV in tonsil-derived lymphocytes. Using these tools, we have recently discovered that mature plasma cells are highly targeted early in KSHV infection and that KSHV-infected plasma cells display a mixture of latent and lytic infection cycles. The current proposal will test several hypotheses: (1) plasma cell infection serves as an amplification step which is important for the overall establishment of infection in tonsil lymphocytes, (2) the KSHV-encoded cytokine vIL-6 is critical for establishment of KSHV infection in lymphocytes via manipulation of plasma cell biology and (3) the T cell-derived cellular cytokine IL-21 supports KSHV dissemination by driving differentiation of plasma cells, and can partially replace the function of vIL-6 in early infection. The results of this research will provide critical mechanistic details that will enhance our understanding of early events in KSHV transmission and the establishment of KSHV infection in the lymphocyte compartment.