KSHV infection of human tonsillar B cells

KSHV 感染人扁桃体 B 细胞

• 批准号: 8263135
• 负责人: Dean H Kedes
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263135
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Antibodies; Apoptosis; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Biology; Blood Circulation; Cancer Etiology; Cell Survival; Cell physiology; Cells; Cellular Morphology; Characteristics; Coupled; Data; Disease; Distal; Endothelial Cells; Epidemiology; Epigenetic Process; Exposure to; Flow Cytometry; Foundations; Genes; Genetic Transcription; Goals; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Image; Imagery; Immune; Immunoglobulin M; Individual; Infection; Inflammatory; Kaposi Sarcoma; Laboratories; Light; Link; Lymphatic; Lymphoma; Lytic; Malignant Neoplasms; Measures; Modeling; Modification; Molecular Profiling; Multicentric Angiofollicular Lymphoid Hyperplasia; Nature; Oral; Oral cavity; Organ; Organ Transplantation; Orthologous Gene; Pathogenesis; Pathologic; Patients; Pattern; Peripheral; Persons; Phenotype; Play; Population; Predisposition; Proteins; Reporter; Reverse Transcriptase Polymerase Chain Reaction; Role; Route; SECTM1 gene; Saliva; Site; Solid; Sorting - Cell Movement; Source; Staging; Testing; Tonsil; Transcript; Transplant Recipients; Tropism; Viral; Viral Genes; Viral Proteins; Virion; Virus; Work; base; cell type; cytokine; effusion; functional outcomes; gammaherpesvirus; infected B cell; intercellular communication; latency-associated nuclear antigen; latent gene expression; latent infection; peripheral blood; promoter; sarcoma; transmission process; tumor; tumorigenesis; tumorigenic; viral detection

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8) establishes lifelong infection and is the etiologic agent underlying primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma, an endothelial cell-based angiogenic tumor that remains the most prevalent AIDS-associated malignancy worldwide. Although the site for a definitive latent reservoir(s) remains unclear, KSHV can infect B cells in the oral cavity and express a number of viral proteins capable of modulating B cell signaling and survival. Shedding of KSHV in the saliva is frequent in infected individuals and concentrations are often higher than in the peripheral blood. Further, epidemiologic work implicates saliva as a major source for person-to-person viral transmission with infected tonsillar B cells also providing a potential source of spread to distal sites within individuals. In contrast, KSHV-infected B cells in the peripheral circulation are extremely rare in asymptomatic individuals and only slightly less infrequent in patients with early stages of disease. These observations suggest that KSHV may preferentially infect a subset of B cells present in the lymphatic organs of the oral cavity. Our overarching hypothesis is that oral exposure to KSHV leads to selective infection of a specific subset of human tonsillar B cells, effecting phenotypic and functional changes favorable to viral persistence and predictive of pathologic potential. Very little is known about the critical identity and character of KSHV-susceptible B cells in the oral cavity, the nature of the infection, the mechanism underlying differential tropism, or the characteristics of KSHV-induced changes in B cell phenotype and function. We propose to answer these questions. It is our long-term goal to causally link these changes with the expression of specific viral genes and identify those alterations potentially responsible for initiating and sustaining KSHV pathogenesis.) PUBLIC HEALTH RELEVANCE: The most recently discovered cancer causing human herpesvirus, KSHV, underlies at least three severe diseases, two of which affect a group of critical immune cells called "B cells". This virus tends to afflict individuals least able to fightoff infection, including AIDS patients and solid organ transplant recipients. Recent studies indicate that the most likely route of person-to-person transmission of this virus is through saliva and tha B cells in the tonsils may be the major targets that spread the virus within the body. In this gran application, we propose to understand which B cells KSHV targets, the mechanisms underlying B cell infection and, finally, how infection might transform cellular function.

描述（由申请人提供）：卡波西肉瘤相关疱疹病毒 (KSHV)，也称为人疱疹病毒 8 (HHV8)，可造成终生感染，是原发性渗出性淋巴瘤、多中心 Castleman 病和卡波西肉瘤（一种仍然最常见的内皮细胞血管生成肿瘤）的病因 全世界与艾滋病相关的恶性肿瘤。尽管最终潜伏病毒库的位点仍不清楚，但 KSHV 可以感染口腔中的 B 细胞，并表达许多能够调节 B 细胞信号传导和存活的病毒蛋白。在感染者中，KSHV 在唾液中的排出很常见，并且浓度通常高于外周血中的浓度。此外，流行病学研究表明唾液是人与人之间病毒传播的主要来源，受感染的扁桃体 B 细胞也提供了传播到个体远端部位的潜在来源。相比之下，外周循环中感染 KSHV 的 B 细胞在 无症状个体，仅在疾病早期患者中发生率稍低。这些观察结果表明，KSHV 可能优先感染口腔淋巴器官中的 B 细胞亚群。我们的总体假设是，口服 KSHV 会导致人类扁桃体 B 细胞特定亚群的选择性感染，从而影响有利于病毒持久性和病理潜力预测的表型和功能变化。关于口腔中 KSHV 易感 B 细胞的关键特性和特征、感染的性质、差异向性的机制或 KSHV 诱导的 B 细胞表型和功能变化的特征，人们知之甚少。我们建议回答这些问题。我们的长期目标是将这些变化与特定病毒基因的表达联系起来，并确定那些可能导致启动和维持 KSHV 发病机制的变化。） 公共健康相关性：最近发现的导致癌症的人类疱疹病毒 KSHV 是至少三种严重疾病的根源，其中两种疾病影响一组称为“B 细胞”的关键免疫细胞。这种病毒往往会影响最无力抵抗感染的个体，包括艾滋病患者和实体器官移植接受者。最近的研究表明，这种病毒最有可能的人际传播途径是通过唾液，扁桃体中的 B 细胞可能是体内传播病毒的主要目标。在此大型应用中，我们建议了解 KSHV 的目标 B 细胞、B 细胞感染的机制，以及最后，感染如何改变细胞功能。