3-D Oral Mucosa Model for EBV Pathogenesis

描述（由申请人提供）：这项新研究者发起的R 03资助申请的目标是建立一个生理相关的人类口腔粘膜模型，以研究艾滋病患者中重要病原体EB病毒（EBV）的发病机制。EBV是免疫抑制个体中传染性单核细胞增多症以及鼻咽癌、伯基特淋巴瘤和其它B淋巴细胞淋巴瘤的病原体。此外，裂解性EBV复制与口腔毛状白斑病相关，口腔毛状白斑病是舌侧缘上的疣状病变，在相当一部分人类免疫缺陷病毒（HIV）感染个体中发生。由于没有合适的体内或体外口腔粘膜模型系统来研究在高度受控条件下的病毒发病机制，因此对EBV的原发感染、释放和传播的机制知之甚少。本项目采用三维系统开发人口腔粘膜的体外模型，以研究口腔上皮的EBV感染。本研究的具体目的是：（1）建立口腔黏膜异源共培养模型;（2）研究EB病毒在口腔黏膜组织中的感染和复制。一个复杂的人类口腔粘膜模型的建立将提供新的见解EBV感染的口腔粘膜，并导致一个假设驱动的R 01赠款申请解决EBV免疫生物学的口腔上皮。 EB病毒（Epstein-Barr virus，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是免疫抑制个体中传染性单核细胞增多症以及鼻咽癌、伯基特淋巴瘤和其它B淋巴细胞淋巴瘤的病原体。此外，裂解性EBV复制与口腔毛状白斑病相关，口腔毛状白斑病是舌侧缘上的疣状病变，在相当一部分人类免疫缺陷病毒（HIV）感染个体中发生。EBV的原发感染、释放和传播机制尚不清楚。由于没有体外或动物模型存在的EBV，关键的知识差距，关于EBV在体内的发病机制仍然有待回答，包括EBV如何持续，尽管持续的免疫监视和什么事件之前EBV相关的疾病。建立一个复杂的人类口腔粘膜模型将提供新的见解，EB病毒感染的口腔粘膜，并导致假设驱动的研究，解决EB病毒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.