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

摘要/项目摘要 卡波西肉瘤相关疱疹病毒(KSHV)是一种致癌性人类疱疹病毒，可引起卡波西。 在缺乏足够免疫控制的情况下，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艾滋病毒携带者发病率和死亡率的重要原因。 疾病。口腔是KSHV生物学的重要部位，因为唾液被认为是KSHV的主要模式 病毒在人与人之间传播。扁桃体和其他口腔淋巴组织代表着 早期感染事件的解剖部位，因为它们与唾液接触，并含有丰富的靶细胞类型 KSHV感染包括内皮细胞和B淋巴细胞。尽管如此，KSHV在人类扁桃体中的生物学 人们对此仍然知之甚少。我们已经建立了一个广泛的人类扁桃体标本资料库和一个强大的前 扁桃体来源淋巴细胞体内感染KSHV模型。使用这些工具，我们最近发现 成熟浆细胞在KSHV感染早期高度靶向，感染KSHV的浆细胞表现为 潜伏感染周期和裂解感染周期的混合。目前的提议将检验几个假设：(1)浆细胞感染 作为对扁桃体淋巴细胞感染的整体建立很重要的放大步骤， (2)KSHV编码的细胞因子IL-6是通过操纵在淋巴细胞中建立KSHV感染的关键。 (3)T细胞来源的细胞因子IL-21通过驱动KSHV传播 在感染早期可部分替代VIL-6的功能。这样做的结果 研究将提供关键的机制细节，将增强我们对KSHV早期事件的理解 KSHV在淋巴细胞室的传播和感染的建立。

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.