Pathogenic Mechanisms of Bacillus Endophthalmitis

项目概要/摘要 眼内细菌感染（眼内炎）导致大量失明病例 全世界。防止感染期间脆弱的眼组织受损的努力依赖于快速和正确的使用 快速杀死生物体并阻止潜在破坏性炎症的疗法。目前使用的抗生素 可以杀死生物体，但抗炎药的有效性存在争议。目前尚无治疗方法 中和损害眼睛非再生组织的毒素。我们的总体目标是发展 针对并抑制这些事件、保护视力的更有效的治疗方法。 蜡样芽孢杆菌 (Bc) 会引起一种最具炎症性和快速致盲性的疾病 眼内炎。这种常见的环境生物在外伤或血液流动时进入眼睛 感染，也是一种据报道的手术污染物。感染 Bc 的眼睛可能会失明 时间短，因此有效的治疗对于挽救视力至关重要。本提案重点关注机制 与有机体及其在眼睛中的行为有关，并强调了感染之前的事件 严重的视网膜损伤和炎症——此时治疗干预最为有价值。我们 提出了解决眼内炎重要早期事件中 Bc 发病机制的四个目标：  目标 1 将分析触发 Bc 孢子萌发的眼内环境要素。的 将检查眼睛中从孢子到营养状态转化的机制。  目标 2 将进一步探索潜在 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 蜡溶素和不耐热表面成分作为激动剂的作用。  目标 3 将检查眼内炎症是否会促使 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。 目标 4 将检验以下假设：在炎症过程中，Bc 分泌的产物解除了渗透的武装 中性粒细胞。候选者包括超氧化物歧化酶、免疫抑制剂 A 和 cereolysin 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眼内炎患者，治疗效果不佳 通常会导致严重的视力丧失或眼球本身的丧失。因此，识别因素和 对早期疾病事件很重要的途径疾病对于开发新颖有效的治疗方法至关重要 这种致盲感染的选择。

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.