New Models of Endogenous Bacterial Endophthalmitis

描述（由申请人提供）：内源性细菌性眼内炎（EBE）是一种由远处感染部位的生物迁移到眼睛引起的破坏性感染。虽然抗生素和手术治疗眼部细菌感染在过去的几十年里有了很大的改善，但在过去的50年里，EBE的视力结果并没有得到改善。EBE风险最大的人群包括免疫功能低下的患者（包括糖尿病患者）或接受免疫治疗的患者、长期使用留置装置的患者和静脉注射药物滥用者。潜在的双侧失明使EBE成为最具破坏性和毒性的眼部感染之一。改善EB临床结果的关键障碍是缺乏对疾病致病机制的了解。这一重要目标可以通过对EBE实验模型的研究来实现；但是，目前不存在这种预算外开支模式。细菌从血液中迁移到眼睛的机制尚不清楚。我们的研究试图通过开发和描述新的预算外活动模型来填补现有的信息差距。肺炎克雷伯菌和金黄色葡萄球菌是导致多种感染的机会性病原体，是EBE最常见的病因。越来越多的肺炎克雷伯菌和金黄色葡萄球菌EBE病例被报道，特别是在糖尿病患者中。本R21提案旨在开发和表征小鼠肺炎克雷伯菌和金黄色葡萄球菌感染的新实验模型。这些模型将包括一个链脲佐菌素诱导的糖尿病小鼠模型，以分析糖尿病对感染从血液扩散到眼睛的贡献。根据初步数据显示，血液-视网膜屏障通透性更高的糖尿病小鼠EBE发病率更高，我们假设糖尿病眼环境促进细菌迁移到眼睛，导致EBE。然而，由于糖尿病引起许多可能导致EBE发展的系统和局部变化，关于糖尿病眼环境的哪个方面最重要的问题仍然存在。发展具有良好特征的EBE模型将使我们能够解决这些问题。拟议的研究是我们长期的眼内炎研究项目的一个合乎逻辑的结果，我们有能力提供新的和有价值的信息，这将推进我们的长期目标，即详细了解导致细菌向眼睛迁移和进入眼睛以及EBE期间眼睛损伤和炎症的特定因素（细菌和宿主）。通过引入新的感染模型，我们的研究结果将对眼部传染病领域产生积极影响，这些模型最终可用于测试治疗方法，以改善这种致盲疾病的临床结果。

DESCRIPTION (provided by applicant): Endogenous bacterial endophthalmitis (EBE) is a devastating infection caused by the migration of organisms into the eye from a distant site of infection. Although antibiotic and surgical treatment of ocular bacterial infections has greatly improved over the past few decades, the visual outcome of EBE has not improved in the past ~50 years. Populations at greatest risk for EBE include immunocompromised patients (including diabetics) or those on immunotherapy, those with prolonged indwelling devices, and intravenous drug abusers. The potential for bilateral blindness makes EBE one of the most devastating and virulent ocular infections. A critical barrier to progress in improving the clinical outcome of EB is a lack of knowledge about the pathogenic mechanisms of disease. This important goal could be achieved through studies in experimental models of EBE; however, no such EBE model currently exists. The mechanisms of bacterial migration into the eye from the bloodstream are not well understood. Our research seeks to fill that existing information gap by developing and characterizing new models of EBE. K. pneumoniae and S. aureus are opportunistic pathogens that cause a variety of infections and are the most common etiologic agents of EBE. An increasing number of K. pneumoniae and S. aureus EBE cases are being reported, specifically in diabetic patients. This R21 proposal seeks to develop and characterize new experimental models of K. pneumoniae and S. aureus infection in mice. These models will incorporate a streptozotocin-induced diabetic mouse model to analyze the contribution of the diabetes to the spread of infection from the bloodstream into the eye. Based on preliminary data demonstrating a greater incidence of EBE in diabetic mice with greater blood-retinal barrier permeability, we hypothesize that that the diabetic ocular environment facilitates migration of bacteria into the eye, causing EBE. However, because diabetes causes a number of systemic and local changes that might contribute to EBE development, questions remain as to which aspect of the diabetic ocular environment is most important. Development of well- characterized EBE models will allow us to address those questions. The proposed studies are a logical outgrowth of our long-standing endophthalmitis research program, and we are well positioned to contribute new and valuable information that will advance our long range goal of developing a detailed understanding of the specific factors (bacterial and host) that contribute to bacterial migration toward and into the eye and ocular damage and inflammation during EBE. Our findings will positively impact the ocular infectious disease field by introducing new infection models that can ultimately be used to test therapeutics in an effort to improve the clinical outcome of this blindig disease.