Identifying susceptibility factors for KSHV infection in human tonsil

确定人扁桃体 KSHV 感染的易感因素

基本信息

批准号：
10596565
负责人：
Jennifer E Totonchy
金额：
$ 34.91万
依托单位：
CHAPMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596565
关键词：
Affect Anatomy B-Lymphocytes Biology Cell Line Cell Lineage Cell model Cells Cellular biology Communities Cytokine Signaling Disease Endothelial Cells Etiology Event Frequencies Gene Expression Gene Expression Profile Goals HIV Herpesviridae Herpesviridae Infections Human Human Herpesvirus 8 Immune Immune System Diseases Immunologics In Vitro Incidence Individual Infection Inflammatory Intrinsic factor Kaposi Sarcoma Libraries Link Lymphocyte Lymphoid Tissue Lymphoproliferative Disorders Malignant Neoplasms Modeling Molecular Biology Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Oncogenic Oral Oral cavity Organism Pathogenesis Persons Population Predisposition Primary Cell Cultures Process Research Saliva Sampling Site Source Specimen Syndrome Techniques Testing Time Tonsil Transplant Recipients Viral Virion Virus cell type co-infection cytokine immunological status insight microbial microbiome mortality new therapeutic target novel novel strategies pathogen prevent primary effusion lymphoma transcriptome sequencing 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 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.

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患者的发病率和死亡率的重要原因艾滋病毒。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的人向人传播方式。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富含靶细胞类型对于KSHV感染，包括内皮细胞和B淋巴细胞。尽管如此，人类KSHV的生物学扁桃体仍然很熟悉。我们已经成功地将各种原代细胞谱系与人隔离了扁桃体标本，并为扁桃体衍生的淋巴细胞和非 - 淋巴细胞细胞系。当前的建议将利用我们扁桃体淋巴细胞标本和细胞系的图书馆为了探索这个利基市场中KSHV传播的基本生物学。使用离体易感性的扁桃体衍生的B淋巴细胞作为每个扁桃体标本对KSHV感染的总体敏感性的替代物，我们将使用各种分子和细胞生物学技术来检查可能影响KSHV感染新宿主的能力。这些因素包括：（1）宿主免疫学参数（2）宿主基因表达参数（3）病毒共同感染和（4）细菌共感染/微生物组社区。我们还将研究KSHV在早期感染期间如何操纵宿主细胞因子信号传导确定是否可以操纵细胞因子以限制扁桃体的KSHV感染的建立淋巴细胞。最后，我们将确定KSHV如何在扁桃体衍生的细胞类型内和之间传播确定哪些细胞类型（1）对于将感染转移到疾病相关的细胞类型（2）潜力（2） KSHV脱落到唾液中的来源。这项研究的结果将提供有关因素的关键信息影响KSHV传播，并将重点介绍可以利用的新型治疗靶标的 KSHV在人口中的传播。