New Models of Endogenous Bacterial Endophthalmitis

描述(申请人提供)：内源性细菌性眼内炎(EBE)是一种毁灭性的感染，由微生物从远处的感染部位迁移到眼睛内而引起。尽管在过去的几十年里，眼部细菌感染的抗生素和手术治疗有了很大的进步，但EBE的视力结果在过去的50年里并没有改善。EBE风险最高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、使用长时间留置装置的患者和静脉吸毒者。双眼失明的可能性使EBE成为最具破坏性和最致命的眼部感染之一。在改善EB的临床结局方面取得进展的一个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；然而，目前还不存在这样的EBE模型。细菌从血液迁移到眼睛的机制还不是很清楚。我们的研究试图通过开发和描述新的EBE模型来填补现有的信息缺口。肺炎克雷伯菌和金黄色葡萄球菌是引起各种感染的条件致病菌，是EBE最常见的病原体。越来越多的肺炎克雷伯菌和金黄色葡萄球菌EBE病例被报告，特别是在糖尿病患者中。这份R21提案旨在开发和表征肺炎克雷伯菌和金黄色葡萄球菌在小鼠中感染的新实验模型。这些模型将包括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传播到眼睛的贡献。根据初步数据显示，在血-视网膜屏障通透性较高的糖尿病小鼠中，EBE的发生率更高，我们假设糖尿病眼环境促进细菌迁移到眼睛，导致EBE。然而，由于糖尿病引起了许多可能有助于EBE发生的全身性和局部性变化，糖尿病眼环境的哪一方面最重要仍是个问题。开发具有良好特征的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眼内炎研究计划的合乎逻辑的结果，我们处于有利地位，能够提供新的有价值的信息，这些信息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)。我们的发现将通过引入新的感染模型，最终可用于测试治疗方法，努力改善这种混合疾病的临床结果，从而对眼部感染疾病领域产生积极影响。

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.