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: 8036989
• 负责人: CHARLES J. SMITH
• 金额: $ 31.78万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036989
• 关键词: Abdominal Abscess; Abdominal Infection; Abscess; Acute; Address; Affect; Anaerobic Bacteria; Appendicitis; Bacteria; Bacteroides fragilis; Biological Models; Carcinoma; Cells; Colon; Defense Mechanisms; Development; Disease; Diverticulitis; Environment; Equilibrium; Exposure to; Ferritin; Funding; Gene Expression; Genes; Genetic; Goals; Greater sac of peritoneum; Health; Homeostasis; Human; Human body; Immune response; In Vitro; Indigenous; Infection; Intervention; Intestines; Intra-abdominal; Invaded; Iron; Iron-Sulfur Proteins; Lead; Learning; Measurement; Measures; Mediating; Membrane Proteins; Metabolic; Metabolism; Microbe; Mus; Necrosis; Nutritional; Operative Surgical Procedures; Opportunistic Infections; Organism; Oxidation-Reduction; Oxidative Stress; Oxygen; Pattern; Perforation; Phase; Physiological; Play; Population; Process; Property; Proteins; Reactive Oxygen Species; Regulation; Regulon; Relative (related person); Research; Resistance; Role; Serum; Site; Stimulus; Stress; Sulfhydryl Compounds; Surface; System; Testing; Thioredoxin; Transcriptional Regulation; Trauma; base; biological adaptation to stress; design; gene induction; in vivo; innovation; insight; macromolecule; microbial; mutant; novel; oxidative damage; prevent; public health relevance; repaired; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Disruption of the defense barriers between the host and its indigenous microflora can lead to opportunistic infections which have a serious impact on human health. Intra-abdominal abscesses are formed following perforation of the bowel often due to appendicitis, diverticulitis, carcinoma, or surgery. These infections are composed of mixed intestinal flora with the indigenous intestinal anaerobe, Bacteroides fragilis as the predominant component. We hypothesized that resistance to oxidative stress is an important factor in the development of these infections. This is because relative to the colon, the peritoneal cavity is an oxygenated environment, and the recruitment of PMNs to the site of infection will result in exposure of B. fragilis to reactive oxygen species. In the current funding period we have documented that there is an acute oxidative stress response which is designed to minimize the immediate affects of oxygen radicals. This is mediated by the regulator OxyR which is necessary for optimal abscess formation in mice. We also have shown that there is a novel, widespread induction of genes associated with metabolism, which occurs when there is extended exposure to oxidative stress. For the current application, we hypothesize that this extended phase and the accompanying expansive induction of metabolic genes is critical for prolonged resistance to oxidative stress and for in vivo survival in extra-intestinal sites. We will learn how this Prolonged Oxidative STress (POST) response promotes adaptation to extended oxidative stress, determine if it is necessary to maintain the organism in a resistant state and elucidate some of the mechanisms that control it. Ultimately we will discover if it enhances persistence in the abscess milieu of necrotic cell debris, viable PMNs, and host serum factors. Three aims will address this central hypothesis. Three specific aims will address this central hypothesis. In specific aim1 we will elucidate the mechanisms that regulate the POST response, determine how it is controlled by stress stimuli, and if it leads to multiple stress resistance. In specific aim 2 we will show that a robust thiol metabolism is an integral component of the POST response and determine if it is needed to survive in vivo. Finally in specific Aim 3 we will examine mechanisms of iron storage and how they help prevent oxidative damage during POST. We will determine if the iron storage proteins can contribute to the repair of iron sulfur proteins and the in vivo expression of their cognate genes will be measured to gain insight into their role during infection. PUBLIC HEALTH RELEVANCE: Every mucosal surface of the human body is inhabited by bacteria that have developed a commensal relationship with their host. Bacteroides fragilis is part of this indigenous, "normal", flora in the colon and the primary goal of this research is learn how it causes intra-abdominal infections after being translocated from the colon due to disease or trauma. The successful completion of this research could lead to the discovery innovative new treatment strategies based on intervention in the pathogenic process or unique properties of the organism.

描述（由申请人提供）：宿主与其本地菌群之间的防御障碍的破坏会导致机会性感染，这会对人类健康产生严重影响。肠内脓肿通常是由于肠炎，憩室炎，癌或手术引起的肠道穿孔后形成的。这些感染由混合肠菌群与土著肠道厌氧菌组成，菌丝叶片作为主要成分。我们假设对氧化应激的抗性是这些感染发展的重要因素。这是因为相对于结肠，腹膜腔是一个氧化环境，将PMN募集到感染部位将导致Fragilis暴露于活性氧。在当前的资金期间，我们记录了存在急性氧化应激反应，该反应旨在最大程度地减少氧气自由基的直接影响。这是由调节剂oxyr介导的，这是小鼠最佳脓肿形成所必需的。我们还表明，与代谢相关的基因有一种新颖的，广泛的诱导，这是在氧化应激的扩展暴露时发生的。对于当前的应用，我们假设这种扩展的相位和随附的代谢基因的膨胀诱导对于延长氧化应激的耐药性和在肠外部位的体内存活至关重要。我们将学习这种延长的氧化应激（POST）反应如何促进对扩展氧化应激的适应，确定是否有必要将生物保持在抗性状态，并阐明某些控制其的机制。最终，我们将发现它是否增强了坏死细胞碎片，可行PMN和宿主血清因子的脓肿环境中的持久性。三个目标将解决这一中心假设。三个具体目标将解决这一中心假设。在特定的目标1中，我们将阐明调节后反应的机制，确定其如何受到应力刺激的控制，以及它是否导致多种应力抗性。在特定目标2中，我们将表明稳健的硫醇代谢是后反应的组成部分，并确定是否需要在体内生存。最后，在特定目标3中，我们将检查铁储存机制以及它们如何帮助预防邮政期间的氧化损伤。我们将确定铁储存蛋白是否可以有助于铁硫蛋白的修复，并将测量其同源基因的体内表达，以深入了解其在感染过程中的作用。 公共卫生相关性：人体的每一个粘膜表面都居住在与宿主建立共同关系的细菌中。细菌脆弱的脆弱是这种土著“正常”的一部分，结肠中的菌群，这项研究的主要目标是了解其因疾病或创伤引起的结肠易位后如何引起腹腔内感染。这项研究的成功完成可能会导致基于在病原过程或生物体的独特特性的干预基于干预的发现创新的新治疗策略。