ROLE OF CELL INTEGRINS IN ADENOVIRAL CONJUNCTIVITIS

大约有50种不同类型的腺病毒(Ad)与大量的人类呼吸道、胃肠道和眼部感染有关。在治疗各种获得性和遗传性疾病的临床试验中，Ad2/5型也被用作基因传递的载体。尽管有大量关于病毒结构及其生命周期的信息，但对与严重眼部感染(流行性角膜结膜炎，EKC)相关的某些Ad类型所使用的受体缺乏了解。具体地说，属于D亚组(AD37、Ad19a、AD8)的Ad类型表现出眼细胞趋向性，并导致EKC。最近的研究表明，AD37识别一个50 kDa的蛋白受体，该受体优先表达于结膜细胞。本研究旨在鉴定AD37受体，并确认其在D亚型腺病毒眼部感染中的作用。进一步的研究还将检查整合素α-v-beta3和α-v-beta3的作用以及细胞信号通路在Ad4诱导的眼部感染中的作用。这些分子是AD2内化的辅助受体；然而，它们在D亚群病毒感染结膜、角膜和其他眼细胞中的作用尚未确定。最后，D亚组ADS与其主要受体或与辅助受体或两者都络合的结构分析将使用冷冻电子显微镜或X射线结晶学进行。这些研究将使我们能够更全面地了解腺病毒感染的多阶段过程。它们还可能导致抗病毒化合物的开发，以限制D亚群腺病毒的眼部感染。

There are approximately 50 different types of adenoviruses (Ad) which are associated with a significant number of human respiratory, gastrointestinal and ocular infections. Ad types 2/5 are also being used as vectors for gene delivery in clinical trials to treat a variety of acquired and inherited diseases. Despite a wealth of information on the virus structure and its life-cycle, there is a lack of knowledge of the receptors used by certain Ad types associated with severe ocular infections (epidemic keratoconjunctivitis, EKC). Specifically, Ad types belonging tO subgroup D (Ad37, Ad19a, Ad8) exhibit ocular cell tropism and cause EKC. Recent studies indicate that Ad37 recognizes a 50 kDa protein receptor that is preferentially expressed on conjunctival cells. This proposal seeks to identify the Ad37 receptor and confirm its role in ocular infection by other subgroup D adenoviruses. Further studies will also examine the role of integrins alpha-v-beta3 and alpha-v-beta3 and cell signaling pathways in Ad4nduced ocular infections. These molecules serve as coreceptors for Ad2 internalization; however, their role in infection of conjunctival, cornea and other ocular cell types by subgroup D viruses, has not been established. Finally, structural analyses of subgroup D Ads complexed with their primary receptor or with coreceptors or both molecules will be performed using cryoelectron microscopy or X-ray crystallography. These studies will allow a more complete understanding of the multistage process of adenovirus infection. They could also lead to the development of antiviral compounds to restrict ocular infection by subgroup D adenoviruses.