Infection of primary B cells by the human lymphomagenic pathogen HHV8

人类淋巴瘤病原体 HHV8 感染原代 B 细胞

• 批准号: 8034767
• 负责人: Lynn M Hassman
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034767
• 关键词: B Cell Proliferation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Biology; Candidate Disease Gene; Cell Survival; Cell physiology; Cells; DNA; Disease; Ensure; Environment; Gene Expression; Goals; Health; Human; Human Herpesvirus 4; Human Herpesvirus 8; Human Virus; Imaging technology; Immune System Diseases; Immunocompromised Host; In Vitro; Individual; Infection; Investigation; Kaposi Sarcoma; Laboratories; Lead; Life; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Memory; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Multimodal Imaging; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevention; Prevention therapy; Process; Reverse Transcriptase Polymerase Chain Reaction; Signal Pathway; Signal Transduction; Viral Genes; Viral Genome; Viral Proteins; Virus; Western Blotting; biomedical scientist; cancer type; cell motility; cell transformation; effusion; gammaherpesvirus; in vivo; infected B cell; insight; intercellular communication; metaplastic cell transformation; mortality; pathogen; protein expression; residence; therapeutic target; tool; tumorigenic

DESCRIPTION (provided by applicant): Primary effusion lymphoma (PEL) and multicentric Castleman's disease arise in immunocompromised patients harboring human herpesvirus 8 (HHV8), the same oncogenic pathogen underlying Kaposi's sarcoma. Like EBV, HHV8 establishes lifelong infection by latently infecting B cells and expresses viral proteins capable of modulating B cell signaling and survival. Yet, in stark contrast to EBV, KSHV-infected cells are extremely rare in asymptomatic individuals, and efficient in vitro infection of B cells with KSHV has proven difficult. This suggests that KSHV may infect a small subset of B cells. The long-term goals of this project are to understand the biology and pathogenesis underlying primary B cell infection, examining the hypothesis that the target B cells may represent a unique environment allowing, in the setting of immunocompromise, cellular transformation. We hope to better understand the rules governing this process, with our initial goals being to: 1. Identify the subset(s) of B cells that support KSHV infection. We will utilize high throughput multimodal imaging technology to identify B cell targets of KSHV infection. Appreciating that infection may alter the B cell phenotype, we will confirm the identity of KSHV targets by isolating B cell subsets prior to infection and comparing the efficiency of infection in each subset. 2. Determine the effects of KSHV infection on B cell survival and function and identify candidate genes responsible for these changes. We will focus initial studies on KSHV-induced changes by examining proliferative capacity, survival and transformation ability in vitro. In parallel to these functional studies, we will use mini-microarrays focused on B cell activation pathways, followed by quantitative RT-PCR and/or western blot, to identify changes in cell signaling pathways that may be responsible for potential phenotypic changes. PUBLIC HEALTH RELEVANCE: Cancers and diseases of the immune cells in patients lead to significant morbidity and mortality throughout the world. Unfortunately, the rules governing how these diseases arise and how a healthy cell transforms into a malignant one remain unclear. By examining in the laboratory human viruses that can cause these types of cancers, it is our hope that we will gain insights into these rules, providing biomedical scientist the tools with which to develop better therapies and preventions.

描述（由申请人提供）：携带人类疱疹病毒8（HHV8）的免疫功能低下的患者出现了一级积液淋巴瘤（PEL）和多中心Castleman病，这是Kaposi Sarcom的基础性致病性病原体。与EBV一样，HHV8通过潜在感染B细胞并表达能够调节B细胞信号传导和存活的病毒蛋白来建立终身感染。然而，与EBV形成鲜明对比的是，在无症状的个体中，KSHV感染的细胞极为罕见，并且有效地在具有KSHV的B细胞的体外感染已被证明很困难。这表明KSHV可能会感染一小部分B细胞。该项目的长期目标是了解原发性B细胞感染的生物学和发病机理，以研究靶B细胞可能代表独特环境的假设，在免疫敏化的环境中允许细胞转化。我们希望更好地了解有关此过程的规则，我们的最初目标是：1。确定支持KSHV感染的B单元的子集。我们将利用高吞吐量多模式成像技术来识别KSHV感染的B细胞靶标。欣赏感染可能会改变B细胞表型，我们将通过在感染前隔离B细胞子集并比较每个子集中的感染效率来确认KSHV靶标的身份。 2。确定KSHV感染对B细胞存活和功能的影响，并确定负责这些变化的候选基因。我们将通过在体外检查增殖能力，生存和转化能力来重点研究KSHV诱导的变化。与这些功能研究并行，我们将使用专注于B细胞激活途径的迷你微阵列，然后使用定量的RT-PCR和/或Western blot来识别可能导致潜在表型变化的细胞信号传导途径的变化。公共卫生相关性：患者免疫细胞的癌症和疾病导致全世界显着发病和死亡。不幸的是，管理这些疾病是如何出现的规则以及健康细胞如何转化为恶性肿瘤的规则尚不清楚。通过检查可能引起这些类型癌症的实验室人类病毒，我们希望我们能深入了解这些规则，从而为生物医学科学家提供开发更好的疗法和预防性的工具。