Identifying susceptibility factors for 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患有 艾滋病毒--疾病。口腔是KSHV生物学的重要部位，因为唾液被认为是主要的 病毒在人与人之间传播的方式。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，并且含有丰富的靶细胞类型 对于KSHV感染，包括内皮细胞和B淋巴细胞。尽管如此，KSHV在人类体内的生物学 扁桃体仍然知之甚少。我们已经成功地从人类体内分离出多种原代细胞系。 并建立了扁桃体来源的淋巴细胞和非扁桃体来源的淋巴细胞的体外感染模型。 淋巴细胞系。目前的建议将利用我们的扁桃体淋巴细胞样本和细胞系资料库。 以探索KSHV在这一利基领域传播的基础生物学。利用体外敏感度 扁桃体来源的B淋巴细胞作为每个扁桃体样本对KSHV感染的总体易感性的替代， 我们将使用各种分子和细胞生物学技术来检查样本内在因素，这些因素可能 影响KSHV感染新人类宿主的能力。这些因素包括：(1)宿主免疫学 参数(2)宿主基因表达参数(3)病毒联合感染和(4)细菌联合感染/微生物组 社区。我们还将研究KSHV在早期感染过程中如何操纵宿主细胞因子信号，以便 确定是否可以操纵细胞因子来限制扁桃体中KSHV感染的建立 淋巴细胞。最后，我们将确定KSHV如何在扁桃体来源的细胞类型内和之间传播 确定哪些细胞类型是(1)将感染转移到与疾病相关的细胞类型的重要因素(2)潜力 KSHV的来源脱落到唾液中。这项研究的结果将提供有关因素的关键信息 影响KSHV传播，并将突出可用于限制KSHV传播的新治疗靶点 KSHV在人群中的传播。

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 successfully isolated a variety of primary cell lineages from human tonsil specimens and have developed robust in vitro infection models for tonsil-derived lymphocytes and non- lymphocyte cell lines. The current proposal will leverage our library of tonsil lymphocyte specimens and cell lines in order to explore the fundamental biology of KSHV transmission in this niche. Using ex vivo susceptibility of tonsil-derived B lymphocytes as a surrogate for overall susceptibility of each tonsil specimen to KSHV infection, we will use a variety of molecular and cell biology techniques to examine sample-intrinsic factors that may influence the ability of KSHV to infect a new human host. These factors include: (1) host immunological parameters (2) host gene expression parameters (3) viral co-infections and (4) bacterial co-infections/microbiome communities. We will also examine how KSHV manipulates host cytokine signaling during early infection in order to determine whether cytokines can be manipulated to limit the establishment of KSHV infection in tonsil lymphocytes. Finally, we will determine how KSHV spreads within and between tonsil-derived cell types and determine which cell types are (1) important for transferring infection to disease-relevant cell types (2) potential sources of KSHV shedding into saliva. The results of this research will provide critical information about factors influencing KSHV transmission, and will highlight novel therapeutic targets that can be exploited to limit the spread of KSHV within the human population.