EPSTEIN-BARR VIRUS INFECTION OF MUCOSAL EPITHELIUM

粘膜上皮的 Epstein-Barr 病毒感染

• 批准号: 3197067
• 负责人: JOHN W SIXBEY
• 金额: $ 9.56万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3197067
• 关键词: B lymphocyte; Epstein Barr virus; antiviral antibody; cell differentiation; epithelium; gene expression; genetic manipulation; genetic promoter element; genetically modified animals; laboratory mouse; latent virus infection; leukocyte activation /transformation; molecular cloning; nasopharyngeal neoplasms; oral leukoplakia; oral mucosa; polymerase chain reaction; secretory immune system; tissue /cell culture; viral carcinogenesis; virus DNA; virus genetics; virus infection mechanism; virus replication

The long term goal of the proposed research is to identify virologic, immunologic and cellular factors, unique to human mucosa, which contribute to EBV persistence and to mechanisms of pathogenesis. EBV's disease manifestations point to the importance of viral interactions in human mucosa: nasopharyngeal carcinoma and oral hairy leukoplakia (characterized by EBV latency and an aggressively replicative infection, respectively) are epithelial diseases. African Burkitt's lymphoma, with its unusual tissue distribution, is a malignancy of the mucosal-associated lymphoid tissue. Because EBV's two tissue tropisms suggest that the virus may take advantage of the close functional relations between epithelial and lymphoid elements of the common mucosal immune system, we propose the following aims to reach our long term goals: 1) Elucidation of the role of virus-specific IgA in EBV pathogenesis; 2) examination of the role of cellular factors in the regulation of the EBV life cycle in mucosal epithelium; 3) determination of molecular and biological characteristics of EBV variants in the epithelial tissue of oral hairy leukoplakia. Polyclonal human IgA to EBV as well as IgA monoclonal antibodies to the major glycoprotein of EBV (gp350) will be used to analyze "neutralization" of EBV infectivity for lymphocytes and concurrent IgA-enhanced viral entry into epithelial cells. The possibility of an immune-induced shift in EBV tissue tropisms has tremendous implications for immunization strategy as well as for general concepts of viral pathogenesis. The relation between state of cell differentiation and viral gene expression will be analyzed, first in epithelial tissues of transgenic mice by linking select EBV promoters to beta galactosidase coding sequences; second, in diverse populations of human B lymphocytes, by correlating markers of cell activation/differentiation with virus gene expression. These experiments will elucidate mechanisms of viral persistence and how virus may disseminate after primary infection. Finally, the ability of defective viral DNA to contribute to the high level of viral replication seen in hairy leukoplakia will be examined, first by determination of its structure with cloning and polymerase chain reaction analysis, then by use of novel culture techniques to test its in vitro biologic activity. The existence in nature of a defective virus particle with the ability to enhance, not inhibit, replication of the parent strain suggests mechanisms by which a persistent virus may move from latency to active replication.

拟议研究的长期目标是确定病毒学， 免疫和细胞因子，人类粘膜特有的， EB病毒的持久性和发病机制。 EB病毒病 这些表现指出了病毒相互作用在人类中的重要性。 粘膜：鼻咽癌和口腔毛状白斑（特征 分别由EBV潜伏期和侵袭性复制感染）， 上皮疾病 非洲伯基特淋巴瘤，其不寻常的组织 分布，是一种粘膜相关淋巴组织的恶性肿瘤。 因为EB病毒的两种组织嗜性表明病毒可能会利用 上皮细胞和淋巴细胞之间的密切功能关系 的共同粘膜免疫系统，我们提出了以下目标，以达到 我们的长期目标：1）阐明病毒特异性伊加在 EBV发病机制; 2）检查细胞因子在EBV感染中的作用。 粘膜上皮中EBV生命周期的调节; 3）确定 上皮细胞中EB病毒变异体的分子生物学特征 口腔毛状白斑组织。 抗EBV的多克隆人伊加以及抗EBV的伊加单克隆抗体， EBV的主要糖蛋白（gp 350）将用于分析“中和” EBV对淋巴细胞的感染性和同时IgA增强的病毒进入 转化成上皮细胞 EBV免疫诱导转移的可能性 组织嗜性对免疫策略有巨大的影响， 以及病毒发病机制的一般概念。 的关系 分析细胞分化状态和病毒基因表达， 首先在转基因小鼠的上皮组织中， 启动子的β半乳糖苷酶编码序列;第二，在不同的 人B淋巴细胞群，通过相关的细胞标志物 激活/分化与病毒基因表达。 这些实验 将阐明病毒持续存在的机制，以及病毒如何 初次感染后传播。 最后是能力缺陷 病毒DNA有助于高水平的病毒复制， 毛状白斑将检查，首先通过确定其结构 通过克隆和聚合酶链反应分析， 培养技术检测其体外生物活性。 存在 本质上是一种有缺陷的病毒颗粒， 抑制，复制的亲本菌株提出的机制， 持久性病毒可以从潜伏期移动到活跃复制。