KSHV infection of human tonsillar B cells

KSHV 感染人扁桃体 B 细胞

• 批准号: 8606916
• 负责人: Dean H Kedes
• 金额: $ 0.45万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606916
• 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; 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; functional outcomes; gammaherpesvirus; infected B cell; intercellular communication; latency-associated nuclear antigen; latent gene expression; latent infection; peripheral blood; primary effusion lymphoma; 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.)

描述（由申请方提供）：卡波西肉瘤相关疱疹病毒（KSHV），也称为人类疱疹病毒8（HHV 8），可造成终身感染，是原发性渗出性淋巴瘤、多中心Castleman病和卡波西肉瘤（一种基于内皮细胞的血管生成肿瘤，仍是全球最常见的艾滋病相关恶性肿瘤）的潜在病原体。尽管确定的潜伏性储库的位点仍不清楚，但KSHV可感染口腔中的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。KSHV在唾液中的脱落在受感染的个体中是频繁的，并且浓度通常高于外周血。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细胞也是传播到个体远端部位的潜在来源。相比之下，KSHV感染的B细胞在外周循环中是非常罕见的， 无症状的个体，在疾病的早期阶段的患者中仅稍微不常见。这些观察结果表明，KSHV可能优先感染口腔淋巴器官中存在的B细胞亚群。我们的总体假设是，口服暴露于KSHV导致选择性感染的人扁桃体B细胞的一个特定的子集，影响表型和功能的变化，有利于病毒的持久性和预测的病理潜力。关于口腔中KSHV易感B细胞的关键特性和特征、感染的性质、差异向性的潜在机制或KSHV诱导的B细胞表型和功能变化的特征知之甚少。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因果联系起来，并确定那些可能引发和维持KSHV发病机制的改变。