Significance of Corneal Cell Invasion by Bacteria

描述：角膜溃疡是角膜失明最常见的原因之一。接触透镜配戴者是风险最大的人群，当日常配戴软性（水凝胶）镜片时，年发病率约为1/4000，在长期配戴期间增加至约1/500。目前全球有超过9500万隐形透镜配戴者，仅美国就有约3500万。铜绿假单胞菌是最常见的致病性细菌病原体，也是最有可能导致永久性视力丧失的病原体，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的机制，以期开发新的治疗干预和预防策略。 通常，角膜上皮提供有效的屏障以防止细菌渗透。我们提出的发病机制模型是，接触透镜佩戴干扰眼表的先天防御，从而使细菌在没有明显的全层上皮损伤的情况下穿透角膜上皮。初步数据显示，表面活性蛋白D（SP-D）存在于泪液和角膜上皮中，并且这种物质是角膜上皮细胞细菌入侵的关键天然抑制剂，这是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，以检查眼表SP-D及其在限制铜绿假单胞菌感染性方面的活性。 假设在正常条件下，铜绿假单胞菌不侵入角膜上皮细胞，因为眼表面SP-D结合用于侵入的细菌脂多糖外核上的葡萄糖残基，并且接触透镜佩戴通过减少SP-D的眼表面表达促进铜绿假单胞菌穿透角膜上皮。三个具体目标是：1）阐明SP-D抑制铜绿假单胞菌侵入角膜上皮细胞的机制，2）检查接触透镜配戴是否减少正常、受伤和细菌攻击角膜中的眼表面SP-D表达，和3）确定接触透镜配戴/SP-D消耗是否能够使细菌在体内穿透角膜上皮。

DESCRIPTION: 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 approximately 1/4000 when soft (hydrogel) lenses are worn on a daily wear basis, increasing to approximately 1/500 during extended wear. There are currently more than 95 million contact lens wearers worldwide, approximately 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.