EPSTEIN-BARR VIRUS INFECTION OF MUCOSAL EPITHELIUM

粘膜上皮的 Epstein-Barr 病毒感染

• 批准号: 3197068
• 负责人: JOHN W SIXBEY
• 金额: $ 14.83万
• 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/3197068
• 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; nucleic acid sequence; 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，