Staphylococcus Biology in Ocular Infections

项目总结/摘要 细菌性眼部感染在全世界范围内导致大量失明病例。葡萄球菌 金黄色葡萄球菌引起大多数角膜（角膜炎）和眼内（眼内炎， 缓解）。S.金黄色葡萄球菌在其表面上产生几种粘附素，这些粘附素有助于组织附着、表面成分 引发先天免疫途径和炎症，以及破坏屏障和杀死免疫系统的毒素。 细胞这些毒力因子的协调合成有助于生物体在宿主中存活，并且宿主是 通常受到负面影响。在眼睛里，这可能表现为角膜的痛苦损伤或不可逆转的 视网膜受损，导致严重视力丧失。更糟糕的是，S。金黄色葡萄球菌被认为是严重 疾病控制和预防中心的抗生素耐药性威胁在美国的名单上的威胁。MRSA和多药耐药性现在 常见于眼部分离株，增加了难以治疗的眼部感染的风险。 我们和其他人已经研究了眼部细菌感染的致病机制。为 S.金黄色葡萄球菌、动物感染模型和眼细胞系已用于研究上述领域。 我们对哪些毒素损害角膜和视网膜以及哪些先天途径 与角膜和眼内炎症有关。本建议的重点是涉及的因素， 最早的事件在S。金黄色葡萄球菌眼部感染，迄今为止，这些事件引起的关注最少。 这个新的R 01建议是基于全局假设，即协调调节S。金黄色 粘附素和毒素有助于粘附于组织，破坏屏障，并逃避急性免疫反应。 反应科学前提是基于初步和已发表的数据，表明：1）粘附素 在S.金黄色葡萄球菌表面，当不存在时，减少与角膜细胞的粘附，2）白细胞毒素，当不存在时，减少 角膜炎和眼内炎的毒力;金黄色葡萄球菌对血视网膜屏障的破坏似乎是 粘附素和毒素介导的。这些领域的调查在三个独立的，但相关的目标集中在早期 事件在S。金黄色角膜炎和眼内炎。我们将使用特征良好的S。金黄色葡萄球菌毒力因子- 缺陷突变体和可行的体外和体内感染模型，在严格和直接的实验 旨在定义S.金黄色葡萄球菌因素在这些事件中很重要。 对于眼部感染的患者，无效的治疗往往等同于视力丧失。我们的方法 在我们的领域解决这些差距是创新的，相关的，并将移动眼部感染 通过对S.金黄色葡萄球菌因子负责粘附到组织和规避 急性反应，可能会发现导致更合理使用或发展的目标， 用于预防和治疗感染的治疗剂。这些研究是我们视觉的逻辑延伸， 感染研究计划，我们有能力提供新的重要信息， 改善预防感染和保护视力的选择。

PROJECT SUMMARY / ABSTRACT Bacterial eye infections cause a significant number of cases of blindness worldwide. Staphylococcus aureus causes a majority of these infections of the cornea (keratitis) and interior of the eye (endophthal- mitis). S. aureus produces several adhesins on its surface which aid in tissue attachment, surface components which trigger innate immune pathways and inflammation, and toxins which disrupt barriers and kill immune cells. The coordinated synthesis of these virulence factors aids the organism in host survival, and the host is usually negatively affected. In the eye, this can manifest as a painfully damaged cornea or irreversibly damaged retina, resulting in significant vision loss. To make matters worse, S. aureus is considered a Serious Threat on the CDC’s list of Antibiotic Resistance Threats in the US. MRSA and multidrug resistance are now common in ocular isolates, elevating the risk of ocular infections that are difficult to treat. We and others have investigated the pathogenic mechanisms underlying ocular bacterial infections. For S. aureus, animal infection models and ocular cell lines have been used to investigate the areas noted above. We have a very good idea of which toxins damage the cornea and retina and which innate pathways are involved in corneal and intraocular inflammation. This proposal is focused on the factors involved in the earliest events in S. aureus ocular infections, events that, to date, have drawn minimal attention. This new R01 proposal is based on the global hypothesis that coordinated regulation of S. aureus adhesins and toxins facilitate adherence to tissue, barrier breach, and escape from the acute immune response. The scientific premise is based on preliminary and published data demonstrating that: 1) adhesins on the S. aureus surface, when absent, reduce adhesion to corneal cells, 2) leukotoxins, when absent, reduce virulence in keratitis and endophthalmitis, and 3) S. aureus breach of the blood-retina barrier appears to be adhesin- and toxin-mediated. These areas are investigated in three separate but related aims focused on early events in S. aureus keratitis and endophthalmitis. We will use well-characterized S. aureus virulence factor- defective mutants and feasible in vitro and in vivo infection models in rigorous and straightforward experiments designed to define the S. aureus factors important in these events. For patients with eye infections, ineffective treatment often equates with vision loss. Our approaches to addressing these gaps in our field are innovative, translationally relevant, and will move the ocular infectious disease field forward by identifying the S. aureus factors responsible for adhesion to tissue and circumvention of the acute response, possibly uncovering targets that lead to more rational use or development of therapeutics for prevention and treatment of infection. These studies are a logical extension of our ocular infection research program, and we are well positioned to contribute new and important information that will improve options for preventing infection and preserving vision.