ROLE OF B.FRAGILIS OXYGEN STRESS RESPONSE IN INFECTION

脆弱拟杆菌氧应激反应在感染中的作用

• 批准号: 6832774
• 负责人: CHARLES J. SMITH
• 金额: $ 28.5万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832774
• 关键词: Bacteroides; anaerobic bacteria; antibiotics; antioxidants; bacteria infection mechanism; bacterial genetics; gene expression; gene expression profiling; hyperoxia; infection; ion transport; iron; laboratory mouse; microorganism culture; oxidative stress; thioredoxin; transcription factor; virulence

DESCRIPTION (provided by applicant): The anaerobic organism, Bacteroides fragilis is exceptionally resistant to the toxic effects of oxygen. This resistance can be attributed to induction of an oxidative stress response (OSR) and this response will be studied to document its role in the pathogenesis of Bacteroides infections. It is expected that new mechanisms of free radical protection and novel antioxidant defense strategies will be uncovered. This idea is supported by the fact that B. fragilis has diverged early from other eubacteria and has independently evolved the ability to survive extended exposure to oxygen. Further, since this is an anaerobe it is likely to have stringent requirements for oxygen protection that have resulted in the development of unique highly protective antioxidants. The long-term goals of this research are to understand the basic physiological and genetic processes responsible for B. fragilis oxygen tolerance and how these contribute to virulence. Specific objectives for this proposal are: 1) Delineate novel mechanisms that regulate expression and function of OxyR. OxyR is a redox sensitive transcriptional regulator that governs expression of the OSR. This aim proposes to pursue analysis of unique mechanisms through which OxyR regulates genes expression. In addition we will test the hypothesis that the B. fragilis thioredoxin system is the predominant system for maintaining the cellular redox balance and as such it controls the redox state of oxidative stress responsive regulatory proteins such as OxyR. 2) Characterize the role of Fur homologs in control of the OSR. This aim will test the hypothesis that the three Fur homologs in B. fragilis are required for protection during oxidative stress due to their regulation of metal (Fe) homeostasis and other OSR genes. 3) Elucidate a role for the OSR in B. fragilis infections. This aim will address the hypothesis that the OSR is necessary for initiation of infection and for persistence in the host. Our approach is composed of two phases that will examine the effect of OSR mutations on survival in animal models that mimic the two different stages of infection. Understanding oxygen tolerance may lead to identification of new antibiotic targets effective for treatment of B. fragilis infections. For example, exclusive dependence on thioredoxins for redox control may be a weakness that can be exploited by drugs targeted against thioredoxin reductase.

描述（由申请人提供）：厌氧生物体，菌丝脆弱的脆弱性具有对氧气毒性作用的抗性。这种耐药性可以归因于诱导氧化应激反应（OSR），并且将研究该反应以记录其在菌属感染的发病机理中的作用。预计将发现新的自由基保护和新型抗氧化防御策略的新机制。这一想法得到了以下事实的支持：脆弱的B. fragilis早早与其他花生菌相差，并且独立发展了生存的能力，可扩展暴露于氧气中。此外，由于这是一种厌氧菌，因此可能对氧气保护有严格的要求，这导致了独特的高度保护性抗氧化剂的发展。这项研究的长期目标是了解负责脆弱链球菌氧的基本生理和遗传过程以及这些过程如何促进毒力。该提案的特定目标是：1）描述调节Oxyr表达和功能的新型机制。 Oxyr是控制OSR表达的氧化还原敏感的转录调节剂。该目标建议对Oxyr调节基因表达的独特机制进行分析。此外，我们将检验以下假设：脆弱的硫氧还蛋白系统是维持细胞氧化还原平衡的主要系统，因此它控制了氧化应激响应式调节蛋白（如oxyr）的氧化还原状态。 2）表征毛皮同源物在控制OSR中的作用。该目的将检验以下假设：由于金属（FE）稳态和其他OSR基因的调节，在氧化应激期间需要保护脆性芽孢杆菌中的三个毛皮同源物。 3）阐明OSR在脆弱芽孢杆菌感染中的作用。该目标将解决以下假设：OSR对于启动感染和宿主的持久性是必要的。我们的方法由两个阶段组成，这些阶段将检查OSR突变对模仿感染的两个不同阶段的动物模型中生存的影响。了解氧耐受性可能导致鉴定有效治疗脆弱链球菌感染的新抗生素靶标。例如，对氧化还原控制的硫氧还蛋白的独家依赖性可能是一种弱点，可以用靶向硫氧还蛋白还原酶的药物来利用。