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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062344-07
Application #
7192565
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2001-02-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
7
Fiscal Year
2007
Total Cost
$362,819
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Alverdy, John C (2018) Hypermetabolism and Nutritional Support in Sepsis. Surg Infect (Larchmt) 19:163-167
Alverdy, John C (2018) Microbiome Medicine: This Changes Everything. J Am Coll Surg 226:719-729
Gaines, S; Shao, C; Hyman, N et al. (2018) Gut microbiome influences on anastomotic leak and recurrence rates following colorectal cancer surgery. Br J Surg 105:e131-e141
Zaborin, Alexander; Krezalek, Monika; Hyoju, Sanjiv et al. (2017) Critical role of microbiota within cecal crypts on the regenerative capacity of the intestinal epithelium following surgical stress. Am J Physiol Gastrointest Liver Physiol 312:G112-G122
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Yin, Yushu; Papavasiliou, Georgia; Zaborina, Olga Y et al. (2017) De Novo Synthesis and Functional Analysis of Polyphosphate-Loaded Poly(Ethylene) Glycol Hydrogel Nanoparticles Targeting Pyocyanin and Pyoverdin Production in Pseudomonas aeruginosa as a Model Intestinal Pathogen. Ann Biomed Eng 45:1058-1068
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Alverdy, John C; Hyman, Neil; Gilbert, Jack et al. (2017) Preparing the Bowel for Surgery: Learning from the Past and Planning for the Future. J Am Coll Surg 225:324-332
Hyoju, Sanjiv K; Klabbers, Robin E; Aaron, Melissa et al. (2017) Oral Polyphosphate Suppresses Bacterial Collagenase Production and Prevents Anastomotic Leak Due to Serratia marcescens and Pseudomonas aeruginosa. Ann Surg :

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