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?
NIH ExPorter
NIH ExPorter