权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

EPSTEIN BARR VIRUS INFECTION OF MUCOSAL EPITHELIUM

粘膜上皮的 Epstein Barr 病毒感染

基本信息

批准号：
2094669
负责人：
JOHN W SIXBEY
金额：
$ 15.92万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-05-01 至 1995-07-01
项目状态：
已结题

项目摘要

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.

这项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，对对EBV的持久性和发病机制进行了探讨。EB病毒病症状表明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)是上皮性疾病。非洲伯基特淋巴瘤及其不寻常的组织分布，是一种恶性的粘膜相关淋巴组织。因为EBV的两种组织趋向性表明该病毒可能利用上皮细胞和淋巴系成分之间的密切功能关系对于常见的粘膜免疫系统，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IgA在 EBV的发病机制；2)细胞因子在EB病毒感染中的作用粘膜上皮中EB病毒生命周期的调节；3)测定上皮细胞中EB病毒变异株的分子生物学特性口腔毛状白斑组织。抗EB病毒的多克隆人免疫球蛋白A以及抗EB病毒的人免疫球蛋白A单抗 EBV主要糖蛋白(Gp350)将用于分析“中和” EB病毒对淋巴细胞的感染性和同时存在的IgA增强的病毒进入转化为上皮细胞。EB病毒在免疫诱导下发生转变的可能性组织趋向性对免疫策略具有巨大的影响，因为以及病毒致病的一般概念。两者之间的关系将分析细胞分化状态和病毒基因表达，首次在转基因小鼠的上皮组织中通过连接特定的EBV β半乳糖苷酶编码序列的启动子；第二，在不同的通过细胞相关标志物检测人B淋巴细胞亚群激活/分化与病毒基因表达有关。这些实验将阐明病毒持续的机制以及病毒如何在初次感染后传播。最后，有瑕疵的能力病毒DNA有助于实现高水平的病毒复制毛状白斑将首先通过确定其结构进行检查通过克隆和聚合酶链式反应分析，然后使用新的培养技术检测其体外生物活性。他的存在在本质上有缺陷的病毒颗粒具有增强的能力，而不是亲本菌株的抑制、复制提示了一种机制，即持续病毒可能会从潜伏期转移到主动复制。