Identifying susceptibility factors for 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- 相关的肿瘤是移植患者和患有肿瘤的个体中发病率和死亡率的重要原因。 艾滋病口腔是KSHV生物学的重要部位，因为唾液被认为是KSHV的主要传播途径。 病毒的人际传播方式。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靶细胞类型， 包括内皮细胞和B淋巴细胞。尽管如此，KSHV在人类中的生物学 扁桃体仍然知之甚少。我们已经成功地从人骨髓中分离出多种原代细胞系， 扁桃体标本，并开发了强大的体外感染模型扁桃体衍生的淋巴细胞和非- 淋巴细胞系目前的建议将利用我们的图书馆扁桃体淋巴细胞标本和细胞系 以探索KSHV在该生态位传播的基本生物学。使用离体敏感性 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物， 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， 影响KSHV感染新人类宿主的能力。这些因素包括：（1）宿主免疫 参数（2）宿主基因表达参数（3）病毒共感染和（4）细菌共感染/微生物组 社区.我们还将研究KSHV如何在早期感染过程中操纵宿主细胞因子信号， 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如何在扁桃体衍生细胞类型内和扁桃体衍生细胞类型之间传播， 确定哪些细胞类型是（1）重要的转移感染疾病相关的细胞类型（2）潜在的 KSHV进入唾液的来源。这项研究的结果将提供有关因素的关键信息 影响KSHV传播，并将突出新的治疗靶点，可用于限制 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.