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

基本信息

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
项目类别：
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

项目摘要

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 Kaposi肉瘤相关的疱疹病毒（KSHV）是一种致癌的人疱疹病毒，会导致Kaposi 在没有足够的免疫控制的情况下，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HIV-患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，因为唾液被认为是病毒的人向人传播。扁桃体和其他口服淋巴组织代表逻辑早期感染事件的解剖部位，因为它们与唾液接触并且具有富含靶细胞类型 KSHV感染，包括内皮细胞和B淋巴细胞。尽管如此，人类扁桃体中的KSHV的生物学仍然很了解。我们已经开发了一个广泛的人类扁桃体标本和一个强大的Ex图书馆扁桃体衍生的淋巴细胞中的体内感染模型KSHV。使用这些工具，我们最近发现成熟的浆细胞在KSHV感染中高度靶向，并且KSHV感染的浆细胞显示潜在和裂解感染周期的混合物。当前的建议将检验几个假设：（1）浆细胞感染作为扩增步骤，对于扁桃体淋巴细胞中感染的总体建立非常重要，（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感染至关重要血浆细胞生物学和（3）T细胞衍生的细胞细胞因子IL-21通过驱动来支持KSHV传播浆细胞的分化，可以部分替代VIL-6早期感染的功能。结果的结果研究将提供关键的机械细节，以增强我们对KSHV早期事件的理解淋巴细胞室中的传播和建立KSHV感染。