Role of Toxins in Endophthalmitis

描述（由申请方提供）：眼内炎是眼部手术和地球仪穿透性损伤的潜在致盲并发症。近年来，由于白内障手术病例数量的增加、患者年龄的增加以及微生物对预防措施的抗性的潜在增加以及它们在新透镜材料上形成生物膜的能力，病例数量以及比率已经上升。金黄色葡萄球菌和粪肠球菌的抗生素耐药性已成为相当大的公共卫生关注的问题。这种竞争性更新的目的是继续研究，导致细菌毒素和宿主因子在眼内炎发病机制中的特定作用。一个新的共同PI带来了更多的见解和经验的主机响应项目。中心假设是，在微生物进入前房后，细菌负荷或毒力特性在房水中挫败抗菌因子和清除机制。然后微生物使用相同或其他的毒力特性来促进通过被膜进入后节的移位。在后段，有限的玻璃体流动和抗菌防御导致压倒性的感染和视力丧失，部分原因是干扰正常的宿主细胞防御机制。该假设将通过1）确定毒力性状如何改变通过前房进入眼睛的细菌的运输; 2）确定毒力性状如何挫败先天防御，包括2-防御素抗微生物活性; 3）鉴定在前段和后段中首先响应感染的细胞;确定用于检测侵入的革兰氏阳性细菌的机制;并确定毒力性状是否影响检测或反应;以及4）确定抗细胞凋亡因子1B-晶状体蛋白在S.金黄色葡萄球菌性眼内炎，初步研究显示与视网膜损伤相关。公共卫生相关性：尽管进行了积极的抗菌治疗和手术，眼内炎仍经常导致视力丧失。这一问题因致病微生物的抗生素耐药性增加以及患者人群年龄的增加而加剧。金黄色葡萄球菌和粪肠球菌的抗生素耐药性现在是一个相当大的公共卫生问题。了解哪些细菌和宿主因素在眼内炎的发病机制中起关键作用，将允许开发新的治疗方法和预防策略，为许多接受白内障摘除术或其他眼科手术的患者保留视力。它还可能具有导致治疗和预防其他部位抗生素耐药性感染的新策略的外在价值。

DESCRIPTION (provided by applicant): Endophthalmitis is a potentially blinding complication of ocular surgery and globe penetrating injury. The numbers of cases, as well as the rate, has risen in recent years because of the increasing numbers of cataract surgery cases, increasing age of patients, and potentially increasing resistance of microbes to prophylactic measures and their ability to form biofilms on new lens materials. Antibiotic resistance among Staphylococcus aureus and Enterococcus faecalis has become an issue of considerable public health concern. This competing renewal aims to continue research that has led to the delineation of specific roles of bacterial toxins and host factors in the pathogenesis of endophthalmitis. A new Co-PI brings additional insights and experience on the host response to the project. The central hypothesis is that after microbes enter the anterior chamber, bacterial load or virulence traits foil antimicrobial factors and clearance mechanisms in the aqueous. Microbes then use the same or other virulence traits to promote translocation through the capsule into the posterior segment. In the posterior segment, limited vitreous flow and antimicrobial defenses lead to an overwhelming infection and vision loss stemming in part from interference with normal host cell defense mechanisms. This hypothesis will be tested by 1) Determining how virulence traits alter trafficking of bacteria entering the eye through the anterior chamber; 2) Determining how virulence traits foil innate defenses including 2-defensin antimicrobial activities; 3) Identifying the cells first to respond in the anterior and posterior segments to infection; determining the mechanism for detection of invading gram positive bacterium; and determining whether virulence traits affect detection or response; and 4) Determining how an antiapoptotic factor, 1B-crystallin, is cleaved during S. aureus endophthalmitis, which correlates in preliminary studies with retinal damage. PUBLIC HEALTH RELEVANCE: Endophthalmitis frequently leads to vision loss, despite aggressive antimicrobial therapy and surgery. This problem is exacerbated by increasing antibiotic resistance of the offending microbe, and the increasing age of the patient population. Antibiotic resistance among Staphylococcus aureus and Enterococcus faecalis is now an issue of considerable public health concern. Understanding which bacterial and host factors play critical roles in the pathogenesis of endophthalmitis will permit new therapeutic approaches and preventive strategies to be developed, preserving vision for many patients undergoing cataract extraction or other ocular surgery. It may also have the extrinsic value of leading to new strategies for the treatment and prevention of antibiotic resistant infection at other sites as well.