Pseudomonas' effects on the gut barrier from surgery

假单胞菌对手术后肠道屏障的影响

• 批准号: 7337799
• 负责人: John C Alverdy
• 金额: $ 1.29万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337799
• 关键词: Agonist; Antibiotics; Bacterial Adhesins; Binding; Caco-2 Cells; Caenorhabditis; Cells; Critical Illness; Cytotoxin; Data; Defect; Elastases; Epithelial; Exotoxins; Genes; Gram-Negative Bacteria; Heat-Shock Response; Host resistance; Human; Hypoxia; Indolent; Interferon Type II; Intestines; Lead; Lectin; Mass Spectrum Analysis; Mediator of activation protein; Membrane; Methods; Modeling; Molecular; Morphine; Mus; Nosocomial Infections; Operative Surgical Procedures; Opioid; Opioid Receptor; Organism; Pancreatic Elastase; Pathogenesis; Patients; Permeability; Phenotype; Predisposition; Process; Pseudomonas; Pseudomonas aeruginosa; Rate; Receptor Gene; Reporter Genes; Reporting; Resistance; Role; Sepsis; Signal Transduction; Stress; Techniques; Testing; Virulence; Virulent; delta opioid receptor; in vivo; intestinal epithelium; mortality; novel; novel therapeutics; pathogen; quorum sensing; receptor; research study; response; therapeutic target

The mere presence of the human opportunistic pathogen, Pseudomonas aeruginosa within the intestinal tract of a critically ill surgical patient, is associated an excessive mortality rate (-50%)¿a more than 3-fold increase above physiologically-matchedpatients who culture negative for this pathogen. In this proposal, we provide strong evidence that within the intestinal tract of a surgicallystressed host, mediators are released that directly signal the molecular machinery of P. aeruginosa to express a virulent and lethal phenotype. We hypothesize that specific host stress-derived Bacterial Signaling Compounds (BSCs), includingopioid agonists (morphine, kappa and delta receptor agonists) and Interferon-gamma (IFN-y), are released into the intestinal tract in response to surgical stress. We further hypothesize that these compounds directly bind to specific bacterial membrane receptors on P. aeruginosa that lead to the expression of the quorum sensing- dependent virulence determinant, the PA-I lectin. We have previously demonstrated that expression of PA-I in P. aeruginosa within the intestinal tract of a surgically stressed creates a lethal phenotype in this pathogen, inducing a profound epithelial permeability defect to its potent cytotoxins. Therefore, the Specific Aims of this application are:1) To define the genes and receptors that are required for P. aeruginosa to express PA-I in response to opioid agonists and IFN-y; 2) To test the hypothesis that opioid agonists and IFN-y signal P. aeruginosa to express a more virulent phenotype against the intestinal epithelium through the action of its PA-I lectin; and 3) To isolate, identify, and purify additional host-derived bacterial signaling compounds released into the intestine during stress that signal P. aeruginosa to express the PA-I lectin. A detailed understanding of the moleculardialogue that develops between a surgically stressed host and a classic opportunist like P. aeruginosa will lead to novel therapeutic targets in this highly resistant and lethal pathogen and strategies to interdict in the infectious process at its most proximal point.

仅存在人类机会性病原体，铜绿假单胞菌在肠道内 危重的手术患者的区域与超过3倍的死亡率相关（-50％） 高于对这种病原体培养阴性的物理匹配的患者。在这个建议中，我们 提供有力的证据表明，在手术症状宿主的肠道内部，释放了调解人 直接向铜绿假单胞菌的分子机械发出表达毒力和致命的表型。我们 假设特定宿主应力衍生的细菌信号传导化合物（BSC），包括蛋白酶 激动剂（吗啡，Kappa和Delta受体激动剂）和干扰素 - 伽马（IFN-Y）被释放到 响应手术应激的肠道。我们进一步假设这些化合物直接结合 铜绿假单胞菌上的特定细菌受体，导致法定传感器的表达 依赖病毒确定剂，PA-I讲座。我们以前已经证明了pa-i的表达 在铜绿假单胞菌中，手术压力的肠道中会在这种病原体中产生致命的表型， 诱导其潜在细胞毒素的深刻上皮渗透性缺陷。因此， 该应用是：1）定义铜绿假单胞菌表达PA-I所需的基因和接收器 回应阿片类药物激动剂和IFN-Y； 2）测试阿片类动力学家和IFN-y信号的假设。 通过其作用 pa-i讲座； 3）隔离，识别和净化其他宿主衍生的细菌信号传导化合物 在压力期间，释放到肠道中，该肠子信号铜绿假单胞菌表达PA-I讲座。详细的 了解在手术压力的宿主和经典之间发展的分子序列 像铜绿假单胞菌这样的机会主义者将导致这种高度抗性和致命性的新型治疗靶标 病原体和在最近端处于传染过程中的策略。