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

定义浆细胞在人扁桃体 KSHV 感染建立中的作用

• 批准号: 10491243
• 负责人: Jennifer E Totonchy
• 金额: $ 34.5万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491243
• 关键词: Anatomy; Antibodies; Automobile Driving; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; Biology; Cell Count; Cell Lineage; Cells; Cellular biology; Disease; Endothelial Cells; Epithelial Cells; Etiology; Event; Exposure to; Genetic Transcription; Goals; HIV; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; Immune System Diseases; Immune system; Immunologics; Individual; Infection; Infectious Agent; Inflammatory; Invaded; Kaposi Sarcoma; Libraries; Link; Lymphatic Endothelial Cells; Lymphocyte; Lymphoid Tissue; Lymphoproliferative Disorders; Lytic; Lytic Phase; Maintenance; Malignant Neoplasms; Mesenchymal; Modeling; Morbidity - disease rate; Mucous Membrane; Multicentric Angiofollicular Lymphoid Hyperplasia; Oncogenic; Oral; Oral cavity; Persons; Plasma Cells; Play; Recombinant Proteins; Research; Role; Saliva; Signal Transduction; Site; Specimen; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Tonsil; Transplant Recipients; Tropism; Viral; Virus; Virus Diseases; Work; base; cell type; cytokine; design; insight; latent infection; mortality; mutant; novel; oral immunology; plasma cell differentiation; primary effusion lymphoma; programs; tool; transmission process; tumor; viral transmission

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.

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，可引起卡波西肉瘤 在缺乏足够的免疫控制的情况下，肉瘤（KS）以及 B 细胞淋巴增殖性疾病。 KSHV- 相关肿瘤是移植患者和 HIV 感染者发病和死亡的一个重要原因。 疾病。口腔是 KSHV 生物学的重要部位，因为唾液被认为是 KSHV 传播的主要方式。 病毒的人际传播。扁桃体和其他口腔淋巴组织代表了逻辑上的 早期感染事件的解剖部位，因为它们与唾液接触并且富含靶细胞类型 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特性 仍然知之甚少。我们开发了一个广泛的人类扁桃体标本库和强大的前 扁桃体来源的淋巴细胞中的体内感染模型KSHV。使用这些工具，我们最近发现 成熟浆细胞在 KSHV 感染早期具有高度针对性，并且 KSHV 感染的浆细胞表现出 潜伏性和裂解性感染周期的混合。目前的提案将检验几个假设：（1）浆细胞感染 作为一个放大步骤，对于扁桃体淋巴细胞感染的整体建立非常重要， (2) KSHV 编码的细胞因子 vIL-6 对于通过操作在淋巴细胞中建立 KSHV 感染至关重要 (3) T 细胞衍生的细胞因子 IL-21 通过驱动 KSHV 传播来支持 KSHV 传播 浆细胞分化，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，从而增强我们对 KSHV 早期事件的理解 KSHV 的传播和在淋巴细胞区室中建立 KSHV 感染。