Immunopathogenesis of Adenovirus Keratitis

腺病毒角膜炎的免疫发病机制

• 批准号: 6780076
• 负责人: James Chodosh
• 金额: $ 1.01万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780076
• 关键词: Adenoviridae; antigen antibody reaction; biological signal transduction; cell migration; cellular immunity; corneal epithelium; corneal stroma; enzyme linked immunosorbent assay; fibroblasts; genetic transcription; human tissue; immunopathology; immunoprecipitation; immunoregulation; inhibitor /antagonist; interleukin 8; keratitis; keratoconjunctivitis; neutrophil; organ culture; polymerase chain reaction; receptor binding

DESCRIPTION (provided by applicant): Ocular infection by subgroup D adenovirus serotypes 8, 19, or 37 causes epidemic keratoconjunctivitis, manifest by acute pseudomembranous conjunctivitis, punctate and macro-epithelial corneal erosions, and delayed-onset subepithelial corneal stromal infiltrates. Subepithelial infiltrates, the hallmark of epidemic keratoconjunctivitis, cause photophobia, foreign body sensation, and reduced vision, and may persist for months to years. On the basis of evidence from our laboratory that adenovirus type 19 infection of human corneal fibroblasts in vitro induces the potent neutrophil chemotactant interleukin-8 (IL-8), we hypothesize that adenoviral subepithelial infiltrates result when infection of superficial keratocytes induces secretion of IL-8 and migration of neutrophils into the corneal stroma. Our long term goal is to understand the interplay between adenoviruses and mechanisms of innate immune response in the human cornea. The specific aims of this proposal are: 1) to test the hypothesis that IL-8 gene transcription in adenovirus-infected human corneal fibroblasts occurs before onset of adenoviral gene transcription, 2) to test the hypothesis that an intracellular signaling cascade mediates adenovirus-induced IL-8 gene transcription in human corneal fibroblasts, and 3) to test the hypothesis that inhibitors of intracellular signaling can be applied to prevent IL-8-induced conical inflammation. The National Plan for Vision Research (1999-2003) by the National Advisory Eye Council noted the "high morbidity and economic costs" of epidemic keratoconjunctivitis (p. 42). Our proposal bridges the gap between studies of corneal immunobiology and corneal infectious diseases and meets a major program objective of the Council: to "analyze the molecular nature of corneal inflammation" (p. 51). The proposed studies are significant because they test novel mechanisms of viral pathogenesis and innate immune defense in the human cornea. Chronic discomfort and reduced vision in epidemic keratoconjunctivitis relate directly to the presence of subepithelial corneal infiltrates. The gaps in our knowledge that this grant intends to fill are: 1) by what mechanism does adenovirus infection stimulate IL-8 production by human corneal fibroblasts; and 2) can signal transduction inhibitors be used to inhibit the innate immune response to adenovirus infection of the human cornea?

描述（由申请人提供）：通过亚组D腺病毒的眼部感染 血清型8、19或37引起流行角膜结膜炎，表现为急性 假膜结膜炎，点状和宏观上皮角膜 侵蚀和延迟发作的上皮下角膜基质浸润。 上皮下浸润，流行角膜结膜炎的标志，导致 恐惧症，异物的感觉和视力降低，可能会持续 几个月到几年。根据我们实验室的证据表明腺病毒 人角膜成纤维细胞体外的19种感染可诱导有效 中性粒细胞趋化剂白介素8（IL-8），我们假设腺病毒病毒 当浅表角膜细胞感染时，会产生上皮下浸润 诱导IL-8的分泌和中性粒细胞迁移到角膜基质中。 我们的长期目标是了解腺病毒与 人角膜中先天免疫反应的机制。具体目的 该提议是：1）检验以下假设：IL-8基因转录 腺病毒感染的人角膜成纤维细胞发生在腺病毒发作之前 基因转录，2）检验细胞内信号的假设 级联介导人角膜中腺病毒诱导的IL-8基因转录 成纤维细胞和3）测试了细胞内抑制剂的假设 信号传导可用于防止IL-8诱导的锥形炎症。 国家咨询眼的《国家视觉研究计划》（1999-2003） 理事会指出流行病的“高发和经济成本” 角膜结膜炎（第42页）。我们的提议弥合了研究 角膜免疫生物学和角膜传染病，并符合一项重大计划 理事会的目的：“分析角膜的分子性质 炎症”（第51页）。提出的研究很重要，因为它们测试了 人类病毒发病机理和先天免疫防御的新型机制 角膜。慢性不适和流行角膜炎的视力降低 直接与上皮下角膜浸润有关。差距 据我们所知，这项赠款打算填写的是：1）通过机制的作用 腺病毒感染刺激人角膜成纤维细胞产生IL-8； 2）可以使用信号转导抑制剂来抑制先天免疫 对人角膜腺病毒感染的反应？