Pseudomonas' effects on the gut barrier from surgery

假单胞菌对手术后肠道屏障的影响

基本信息

批准号：
7192565
负责人：
John C Alverdy
金额：
$ 36.28万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/7192565
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

项目摘要

DESCRIPTION (provided by applicant): 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-matched patients who culture negative for this pathogen. In this proposal, we provide strong evidence that within the intestinal tract of a surgically stressed 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), including opioid agonists (morphine, kappa and delta receptor agonists) and Interferon-gamma (IFN-gamma), 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-gamma; 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 molecular dialogue 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.

描述（由申请人提供）：危重手术患者肠道内仅存在人类机会性病原体铜绿假单胞菌，就会导致极高的死亡率（-50%）——比生理匹配且培养阴性的患者死亡率高出 3 倍多。这种病原体。在这项提议中，我们提供了强有力的证据，证明在手术应激宿主的肠道内，介质被释放，直接向铜绿假单胞菌的分子机制发出信号，以表达有毒和致命的表型。我们假设特定宿主应激衍生的细菌信号化合物 (BSC)，包括阿片类激动剂（吗啡、κ 和 δ 受体激动剂）和干扰素-γ (IFN-gamma)，在手术应激反应中被释放到肠道中。我们进一步假设这些化合物直接与铜绿假单胞菌上的特定细菌膜受体结合，从而导致群体感应依赖性毒力决定簇 PA-I 凝集素的表达。我们之前已经证明，在手术应激的肠道内铜绿假单胞菌中 PA-I 的表达会在该病原体中产生致命表型，从而诱导其强效细胞毒素的严重上皮通透性缺陷。因此，本申请的具体目的是： 1)确定铜绿假单胞菌响应阿片类激动剂和IFN-γ表达PA-I所需的基因和受体； 2) 检验阿片类激动剂和 IFN-y 信号铜绿假单胞菌通过其 PA-I 凝集素的作用表达针对肠上皮的更具毒性的表型的假设； 3)分离、鉴定和纯化在应激期间释放到肠道中的额外的源自宿主的细菌信号化合物，其向铜绿假单胞菌发出信号以表达PA-I凝集素。详细了解手术应激宿主与铜绿假单胞菌等经典机会主义者之间发生的分子对话，将导致针对这种高度耐药和致命的病原体找到新的治疗靶点，并制定在其最近点阻断感染过程的策略。