Role of Toxins in Endophthalmitis

描述(由申请人提供)：眼内炎是眼科手术和眼球穿透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抵抗力和在新的晶状体材料上形成生物膜的能力的潜在增加，病例的数量和比率都有所上升。金黄色葡萄球菌和粪肠球菌之间的耐药性已经成为一个相当大的公共卫生问题。这项竞争性更新旨在继续研究细菌毒素和宿主因素在眼内炎发病机制中的具体作用。新的Co-PI带来了关于东道主对项目反应的更多见解和经验。中心假说是，在微生物进入前房后，细菌负荷或毒力特征会破坏房水中的抗菌因子和清除机制。然后，微生物使用相同或其他毒力特征来促进通过包膜进入后节的易位。在后段，有限的玻璃体血流和抗菌防御导致压倒性的感染和视力丧失，部分原因是干扰了正常的宿主细胞防御机制。这一假说将被1)确定毒力特性如何改变细菌通过前房进入眼睛的运输；2)确定毒力特性如何挫败包括2-防御素抗菌活性在内的先天防御；3)确定在感染的前段和后段首先做出反应的细胞；确定检测入侵的革兰氏阳性菌的机制；以及确定毒力特性是否影响检测或反应；以及4)确定在金黄色葡萄球菌眼内炎过程中如何分解抗凋亡因子1B-晶体蛋白，这与视网膜损伤有关。公共卫生相关性：尽管进行了积极的抗菌治疗和手术，但眼内炎仍经常导致视力丧失。这一问题因有害微生物对抗生素的耐药性增加和患者年龄的增加而加剧。金黄色葡萄球菌和粪肠球菌之间的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，将有助于开发新的治疗方法和预防策略，为许多接受白内障摘除或其他眼科手术的患者保留视力。它还可能具有外部价值，为治疗和预防其他部位的抗生素耐药感染带来新的战略。

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.