Pseudomonas' effects on the gut barrier from surgery

点击翻译按钮获取中文摘要

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.