Pathogenic Mechanisms of Bacillus Endophthalmitis

项目总结/摘要 眼内细菌感染（眼内炎）导致相当数量的失明病例 国际吧在感染过程中，防止脆弱的眼组织受损的努力依赖于迅速和正确地使用 快速杀死生物体并阻止潜在的破坏性炎症的治疗剂。目前使用的抗生素 可以杀死生物体，但抗炎药的有效性是有争议的。当前无治疗 中和毒素，损害眼睛的非再生组织。我们的首要目标是发展 更有效的治疗方法，靶向和抑制这些事件，保护视力。 蜡样芽孢杆菌（Bc）引起一种最具炎症性和迅速致盲的形式， 眼内炎这种常见的环境微生物在创伤或血流中进入眼睛 感染，也是一种外科手术污染物。感染了Bc的眼睛在一种 因此，有效的治疗对挽救视力至关重要。这一建议侧重于机制 与生物体及其在眼睛中的行为有关，并突出显示感染过程中的事件， 显著的视网膜损伤和炎症-此时治疗干预将是最有价值的。我们 提出了四个目标，在眼内炎的重要早期事件中解决Bc发病机制： 第一个目标是分析眼内环境中触发Bc孢子萌发的元素。的 将检查眼睛中从孢子到营养状态的转化所涉及的机制。 本研究目的2将进一步探索潜在的Bc激动剂的先天免疫途径识别。对于TLR2，我们将 阐述肽聚糖脱乙酰化和磷壁酸作为激动剂的作用。对于TLR4，我们将解决 cereolysin和热不稳定表面成分作为激动剂的作用。 第三个目标将检查眼内炎症是否促使Bc在整个眼睛中迁移。 RNASeq数据表明Bc的鞭毛和运动系统在体内高度表达。 目的4将检验以下假设：在炎症过程中，Bc分泌的产物解除了浸润 中性粒细胞候选者包括超氧化物歧化酶、免疫抑制剂A和蜡溶素，以及突变体 将测试每种缺陷的潜在抗中性粒细胞活性。 这些独立但相关的目标是我们正在进行的致病性研究的逻辑延伸。 细菌性眼内炎的潜在机制。对于Bc型眼内炎患者，治疗无效 常常导致严重的视力丧失或地球仪本身的丧失。因此，确定因素和 对早期疾病事件很重要的通路疾病对于开发新的和有效的治疗药物至关重要。 这种致盲性感染的治疗方法

PROJECT SUMMARY / ABSTRACT Intraocular bacterial infections (endophthalmitis) cause a significant number of cases of blindness worldwide. Efforts to prevent damage to delicate ocular tissues during infection rely on swift and proper use of therapeutics to rapidly kill organisms and arrest potentially damaging inflammation. Currently-used antibiotics can kill organisms, but the effectiveness of anti-inflammatory drugs is controversial. No current therapies neutralize toxins which damage nonregenerative tissues in the eye. Our overarching goal is to develop more effective therapeutics which target and inhibit these events, preserving vision. Bacillus cereus (Bc) causes one of the most inflammatory and rapidly blinding forms of endophthalmitis. This common environmental organism enters the eye during trauma or bloodstream infection, and is also a reported surgical contaminant. Eyes infected with Bc can be rendered sightless in a short period of time, so effective treatment is critical to saving vision. This proposal focuses on mechanisms related to the organism and its behavior in the eye, and highlights events during the infection course prior to significant retinal damage and inflammation—a time when therapeutic intervention would be most valuable. We propose four aims that address Bc pathogenesis during important early events in endophthalmitis:  Aim 1 will analyze elements of the intraocular environment that trigger germination of Bc spores. The mechanisms involved in transformation from spore to vegetative state in the eye will be examined.  Aim 2 will further explore innate immune pathway recognition of potential Bc agonists. For TLR2, we will address the role of peptidoglycan deacetylation and teichoic acid as agonists. For TLR4, we will address the role of cereolysin and heat-labile surface components as agonists.  Aim 3 will examine whether intraocular inflammation prompts migration of Bc throughout the eye. RNASeq data suggest that flagellar and motility systems of Bc are highly expressed in vivo.  Aim 4 will test the hypothesis that during inflammation, products secreted by Bc disarm infiltrating neutrophils. Candidates include superoxide dismutase, immune inhibitor A, and cereolysin, and mutants deficient in each will be tested for potential anti-neutrophil activity. These independent but related aims are a logical extension of our ongoing research into the pathogenic mechanisms underlying bacterial endophthalmitis. For Bc endophthalmitis patients, ineffective treatment often results in significant vision loss or loss of the globe itself. Therefore, identifying factors and pathways important to early disease events disease is critical to developing novel and effective therapeutic options for this blinding infection.