Pathogenic Mechanisms of Bacillus Endophthalmitis

项目摘要/摘要 眼内细菌感染(眼内炎)导致相当数量的失明病例 全世界。防止在感染期间对脆弱的眼组织造成损害的努力有赖于迅速和适当地使用 快速杀死微生物和遏制潜在破坏性炎症的治疗方法。当前使用的抗生素 可以杀死生物体，但抗炎药的有效性存在争议。没有目前的治疗方法 中和损害眼睛非再生组织的毒素。我们的总目标是发展 更有效的针对和抑制这些事件的疗法，保护视力。 蜡状芽孢杆菌(BC)引起最严重的炎症和迅速致盲的形式之一 眼内炎。这种常见的环境微生物在创伤或血流过程中进入眼睛。 感染，也是据报道的外科污染物。感染BC的眼睛可能会在一种 时间短，因此有效的治疗是挽救视力的关键。这项提议的重点是机制 与眼睛中的有机体及其行为有关，并突出显示在感染过程中发生的事件 严重的视网膜损伤和炎症--这是治疗干预最有价值的时候。我们 提出四个目标来解决眼内炎早期重要事件中BC的发病机制： Aim 1将分析引发BC孢子萌发的眼内环境因素。这个 我们将研究眼睛中从孢子到营养状态转变的机制。 Aim 2将进一步探索潜在BC激动剂的天然免疫途径识别。对于TLR2，我们将 阐述了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 脑溶素和不耐热表面成分作为激动剂的作用。 Aim 3将检查眼内炎症是否促使BC在整个眼睛内迁移。 RNAseq数据表明，BC的鞭毛和运动系统在体内高度表达。 Aim 4将测试这一假设，即在炎症期间，BC解除武装分泌的产品会渗透 中性粒细胞。候选药物包括超氧化物歧化酶、免疫抑制剂A和脑溶素，以及突变体 每种都缺乏的人将接受潜在的抗中性粒细胞活性测试。 这些独立但相关的目标是我们正在进行的致病机理研究的合理延伸 细菌性眼内炎的发病机制。对于BC眼内炎患者，治疗无效 通常会导致严重的视力丧失或地球本身的丧失。因此，确定因素和 早期疾病事件的重要途径疾病是开发新的有效治疗方法的关键 治疗这种令人眼花缭乱的感染。

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.