3-D Oral Mucosa Model for EBV Pathogenesis

描述(申请人提供)：这位新的研究人员发起R03资助申请的目标是建立一个与人体口腔粘膜生理相关的模型，以研究爱泼斯坦-巴尔病毒(EBV)的发病机制，EBV是艾滋病患者的重要病原体。EBV是传染性单核细胞增多症以及鼻咽癌、Burkitt淋巴瘤和免疫抑制个体中其他B淋巴细胞淋巴瘤的病原体。此外，EBV的裂解复制与口腔毛状白斑有关，口腔毛状白斑是舌头外侧边缘的一种疣样病变，在很大一部分人类免疫缺陷病毒(HIV)感染者中发生。EBV的原发感染、释放和传播机制尚不清楚，因为目前还没有合适的体内或体外口腔粘膜模型系统来研究高度可控条件下的病毒发病机制。为了研究EBV对口腔上皮细胞的感染，本项目利用三维系统建立了人口腔黏膜的体外模型。本研究的具体目的是：(1)利用异种共培养体系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情况。复杂人类口腔黏膜模型的建立将为口腔黏膜EBV感染提供新的见解，并导致假说驱动的R01赠款申请，解决口腔上皮的EBV免疫生物学问题。 公共卫生相关性：爱泼斯坦-巴尔病毒(EBV)EBV是人类的一种重要病原体，给卫生保健系统带来了相当大的成本。EBV是传染性单核细胞增多症以及鼻咽癌、Burkitt淋巴瘤和免疫抑制个体中其他B淋巴细胞淋巴瘤的病原体。此外，EBV的裂解复制与口腔毛状白斑有关，口腔毛状白斑是舌头外侧边缘的一种疣样病变，在很大一部分人类免疫缺陷病毒(HIV)感染者中发生。EBV的原发感染、释放和传播机制尚不清楚。由于目前还不存在EBV的体外或动物模型，关于EBV体内致病机制的关键知识空白仍有待回答，包括EBV如何在持续的免疫监测下持续存在，以及EBV相关疾病之前发生了什么事件。复杂人类口腔黏膜模型的建立将为口腔粘膜EBV感染提供新的认识，并导致对口腔上皮EBV免疫生物学的假说驱动研究。

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.