ROLE OF B.FRAGILIS OXYGEN STRESS RESPONSE IN INFECTION

描述（由申请方提供）：厌氧微生物脆弱拟杆菌对氧气的毒性作用具有极强的抵抗力。这种耐药性可归因于氧化应激反应（OSR）的诱导，将研究这种反应以记录其在拟杆菌感染发病机制中的作用。预计将发现新的自由基保护机制和新的抗氧化防御策略。这一观点得到以下事实的支持：B。fragilis很早就从其它真细菌中分化出来，并独立地进化出在长时间暴露于氧气中的情况下存活的能力。此外，由于这是一种厌氧微生物，它可能对氧气保护有严格的要求，这导致了独特的高保护性抗氧化剂的开发。这项研究的长期目标是了解导致B的基本生理和遗传过程。fragilis氧耐受性以及这些如何有助于毒力。该提案的具体目标是：1）描述调节OxyR表达和功能的新机制。OxyR是一种氧化还原敏感的转录调节因子，控制OSR的表达。这个目标提出了追求分析的独特机制，通过OxyR调节基因的表达。此外，我们将测试的假设，即B。fragilis硫氧还蛋白系统是维持细胞氧化还原平衡的主要系统，因此它控制氧化应激应答调节蛋白如OxyR的氧化还原状态。2)描述毛皮同系物在控制OSR中的作用。这一目的将检验这三种毛皮同系物在B. fragilis由于其调节金属（Fe）稳态和其它OSR基因而在氧化应激期间需要保护。3)阐明OSR在B中的作用。脆弱菌感染这一目标将解决的假设，即OSR是必要的感染开始和持久性在主机。我们的方法由两个阶段组成，将在模拟两个不同感染阶段的动物模型中研究OSR突变对存活率的影响。了解氧耐受性可能会导致识别新的抗生素靶点有效治疗B。脆弱菌感染例如，完全依赖硫氧还蛋白进行氧化还原控制可能是一个弱点，可以利用针对硫氧还蛋白还原酶的药物。

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.