3-D Oral Mucosa Model for EBV Pathogenesis

描述（由申请人提供）：该新研究者发起R03资助申请的目的是建立人类口腔黏膜的生理相关模型，以研究艾滋病患者的重要病原体eb病毒（EBV）的发病机制。EBV是传染性单核细胞增多症以及鼻咽癌、伯基特淋巴瘤和其他免疫抑制个体b淋巴细胞淋巴瘤的病原体。此外，溶出性EBV复制与口腔毛状白斑有关，这是一种位于舌侧边缘的疣样病变，在大部分人类免疫缺陷病毒（HIV）感染的个体中发展。EBV的原发感染、释放和传播机制尚不清楚，因为没有合适的体内或体外口腔黏膜模型系统来研究病毒在高度控制条件下的发病机制。本项目利用三维系统建立人口腔黏膜体外模型，以研究EBV感染口腔上皮。本研究的具体目的是：(1)利用异种共培养系统建立口腔黏膜三维模型；(2)研究EBV在口腔黏膜组织中的感染和复制。建立复杂的人口腔黏膜模型将为EBV感染口腔黏膜提供新的见解，并导致假设驱动的R01拨款申请，解决EBV免疫生物学的口腔上皮。

DESCRIPTION (provided by applicant): The goal of this new investigator initiated R03 grant application is to establish a physiologically relevant model of human oral mucosa in order to study the pathogenesis of Epstein-Barr virus (EBV), an important pathogen in AIDS patients. EBV is the causative agent of infectious mononucleosis as well as nasopharyngeal carcinoma, Burkitt's lymphoma, and other B-lymphocyte lymphomas in immunosuppressed individuals. In addition, lytic EBV replication is associated with oral hairy leukoplakia, a wart-like lesion on the lateral borders of the tongue that develops in a substantial portion of human immunodeficiency virus (HIV)-infected individuals. The mechanisms of primary infection, release, and spread of EBV are poorly understood because there are no suitable in vivo or in vitro oral mucosa model systems to investigate viral pathogenesis under highly controlled conditions. This project undertakes the development of an in vitro model of human oral mucosa using a three-dimensional system in order to study EBV infection of the oral epithelium. The specific aims of the study are: (1) establish a 3-D model of oral mucosa using a heterologous co-culture system, and (2) investigate the infection and replication of EBV in oral mucosa tissue. The establishment of a complex human oral mucosa model will provide new insights into EBV infection of the oral mucosa and lead to a hypothesis-driven R01 grant application addressing EBV immunobiology of the oral epithelium. PUBLIC HEALTH RELEVANCE: Epstein-Barr virus (EBV) EBV is an important pathogen in humans and results in considerable cost to the health care system. EBV is the causative agent of infectious mononucleosis as well as nasopharyngeal carcinoma, Burkitt's lymphoma, and other B-lymphocyte lymphomas in immunosuppressed individuals. In addition, lytic EBV replication is associated with oral hairy leukoplakia, a wart-like lesion on the lateral borders of the tongue that develops in a substantial portion of human immunodeficiency virus (HIV)-infected individuals. The mechanisms of primary infection, release and spread of EBV are poorly understood. Because no in vitro or animal model exists for EBV, critical gaps in knowledge regarding EBV pathogenesis in vivo remain to be answered including how EBV persists in spite of the continuous immune surveillance and what events precede EBV-associated diseases. The establishment of a complex human oral mucosa model will provide new insights into EBV infection of the oral mucosa and lead to hypothesis-driven studies addressing EBV immunobiology of the oral epithelium.