Significance of Corneal Cell Invasion by Bacteria

角膜溃疡是角膜盲最常见的原因之一。接触透镜佩戴者 在风险最高的人群中，当配戴软性（水凝胶）镜片， 日常佩戴基础上，增加到约1/500在长期佩戴。目前有超过9500万 全世界的隐形透镜佩戴者，仅美国就有3500万。铜绿假单胞菌是最 通常分离的致病细菌病原体，最有可能导致永久性视力丧失，因为它 具有高度侵袭性且难以治疗。我们的长期目标是了解 隐形透镜配戴易导致角膜感染，为了开发新的策略， 治疗干预和预防。 通常，角膜上皮提供有效的屏障以防止细菌渗透。的 我们提出的发病机制模型是，接触透镜的佩戴干扰了眼部的先天防御 表面，从而使细菌能够在没有明显的全层角膜上皮的情况下穿透角膜上皮 上皮损伤初步数据显示，表面活性蛋白D（SP-D）存在于泪液中， 角膜上皮，并且该物质是角膜上皮细菌侵入的关键天然抑制剂 细胞，角膜炎发病机制中的重要步骤。因此，该建议提出了一项计划， 眼表面SP-D及其限制铜绿假单胞菌感染性的活性。 假设在正常情况下，铜绿假单胞菌不会侵入角膜上皮细胞 因为眼表面SP-D结合细菌脂多糖外核上的葡萄糖残基， 接触透镜的佩戴通过减少铜绿假单胞菌对角膜上皮的渗透， SP-D的眼表表达。这三个具体目标是：1）阐明SP-D 抑制铜绿假单胞菌对角膜上皮细胞的侵袭，2）检查接触透镜的佩戴是否减少 在正常、受伤和细菌攻击的角膜中的眼表面SP-D表达，和3）确定 接触透镜佩戴/SP-D消耗使得细菌能够在体内穿透角膜上皮。

Corneal ulceration is one of the most common causes of corneal blindness. Contact lens wearers are among those at greatest risk with an annual incidence of ~1/4000 when soft (hydrogel) lenses are worn on a daily wear basis, increasing to ~ 1/500 during extended wear. There are currently more than 95 million contact lens wearers worldwide, -35 million in the US alone. Pseudomonas aeruginosa is the most commonly isolated causative bacterial pathogen, and the most likely to cause permanent vision loss because it is highly aggressive and difficult to treat. Our long-term goal is to understand the mechanisms by which contact lens wear predisposes to corneal infection, with a view towards developing new strategies for therapeutic intervention and prophylaxis. Ordinarily, the corneal epithelium provides an effective barrier against bacterial penetration. The pathogenesis model that we propose is that contact lens wear interferes with innate defenses at the ocular surface, thereby enabling bacteria to penetrate the corneal epithelium in the absence of overt full-thickness epithelial injury. Preliminary data show that surfactant protein D (SP-D) is present in tear fluid and the corneal epithelium, and that this substance is a key natural inhibitor of bacterial invasion of corneal epithelial cells, an important step in the pathogenesis of keratitis. This proposal, therefore, advances a plan to examine ocular surface SP-D and its activities in limiting the infectivity of P. aeruginosa. The hypothesis is that under normal conditions P. aeruginosa does not invade corneal epithelial cells because ocular surface SP-D binds glucose residues on bacterial lipopolysaccharide outer core that are used for invasion, and that contact lens wear promotes P. aeruginosa penetration of corneal epithelium by reducing ocular surface expression of SP-D. The three specific aims are; 1) to elucidate the mechanism by which SP-D inhibits P. aeruginosa invasion of corneal epithelial cells, 2) to examine whether contact lens wear reduces ocular surface SP-D expression in normal, wounded and bacterial challenged corneas, and 3) to determine if contact lens wear/SP-D depletion enables bacterial penetration through the corneal epithelium in vivo.