ROLE OF CELL INTEGRINS IN ADENOVIRAL CONJUNCTIVITIS

大约有50种不同类型的腺病毒（Ad）与许多人类呼吸道、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，Ad 2/5型也被用作基因传递的载体。尽管关于病毒结构及其生命周期的信息丰富，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。具体来说，属于tO亚群D的Ad型（Ad37, Ad19a, Ad8）表现出眼细胞的亲和性并引起EKC。最近的研究表明，Ad37识别一个50 kDa蛋白受体，该受体优先在结膜细胞上表达。本研究旨在鉴定Ad37受体并确认其在其他D亚群腺病毒眼部感染中的作用。进一步的研究还将研究整合素α -v- β 3和α -v- β 3以及细胞信号通路在ad4诱导的眼部感染中的作用。这些分子作为Ad2内化的辅助受体；然而，它们在结膜、角膜和其他眼细胞类型被D亚群病毒感染中的作用尚未确定。最后，将使用冷冻电子显微镜或x射线晶体学对D亚群Ads与主受体或辅受体或两者络合的结构进行分析。这些研究将使我们对腺病毒感染的多阶段过程有更全面的了解。它们还可能导致抗病毒化合物的发展，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.