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。隐形眼镜佩戴者是风险最大的人群之一，如果每天佩戴软性（水凝胶）隐形眼镜，每年的发病率约为1/4000，如果长时间佩戴，则增加到约1/500。目前全球有超过9500万隐形眼镜佩戴者，仅在美国就有大约3500万。铜绿假单胞菌是最常见的致病菌，也是最可能导致永久性视力丧失的细菌，因为它具有很强的侵袭性，难以治疗。我们的长期目标是了解隐形眼镜佩戴易导致角膜感染的机制，以期制定新的治疗干预和预防策略。

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.