skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Abstract

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8–driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409591
Report Number(s):
BNL-114643-2017-JA¿¿¿
Journal ID: ISSN 0027-8424
DOE Contract Number:  
SC0012704
Resource Type:
Journal Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 1; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Flitter, Becca A., Hvorecny, Kelli L., Ono, Emiko, Eddens, Taylor, Yang, Jun, Kwak, Daniel H., Bahl, Christopher D., Hampton, Thomas H., Morisseau, Christophe, Hammock, Bruce D., Liu, Xinyu, Lee, Janet S., Kolls, Jay K., Levy, Bruce D., Madden, Dean R., and Bomberger, Jennifer M. Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. United States: N. p., 2016. Web. doi:10.1073/pnas.1610242114.
Flitter, Becca A., Hvorecny, Kelli L., Ono, Emiko, Eddens, Taylor, Yang, Jun, Kwak, Daniel H., Bahl, Christopher D., Hampton, Thomas H., Morisseau, Christophe, Hammock, Bruce D., Liu, Xinyu, Lee, Janet S., Kolls, Jay K., Levy, Bruce D., Madden, Dean R., & Bomberger, Jennifer M. Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. United States. doi:10.1073/pnas.1610242114.
Flitter, Becca A., Hvorecny, Kelli L., Ono, Emiko, Eddens, Taylor, Yang, Jun, Kwak, Daniel H., Bahl, Christopher D., Hampton, Thomas H., Morisseau, Christophe, Hammock, Bruce D., Liu, Xinyu, Lee, Janet S., Kolls, Jay K., Levy, Bruce D., Madden, Dean R., and Bomberger, Jennifer M. Thu . "Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators". United States. doi:10.1073/pnas.1610242114.
@article{osti_1409591,
title = {Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators},
author = {Flitter, Becca A. and Hvorecny, Kelli L. and Ono, Emiko and Eddens, Taylor and Yang, Jun and Kwak, Daniel H. and Bahl, Christopher D. and Hampton, Thomas H. and Morisseau, Christophe and Hammock, Bruce D. and Liu, Xinyu and Lee, Janet S. and Kolls, Jay K. and Levy, Bruce D. and Madden, Dean R. and Bomberger, Jennifer M.},
abstractNote = {Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8–driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF.},
doi = {10.1073/pnas.1610242114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 1,
volume = 114,
place = {United States},
year = {2016},
month = {12}
}

Works referenced in this record:

Long-Distance Delivery of Bacterial Virulence Factors by Pseudomonas aeruginosa Outer Membrane Vesicles
journal, April 2009


Eicosanoid storm in infection and inflammation
journal, July 2015

  • Dennis, Edward A.; Norris, Paul C.
  • Nature Reviews Immunology, Vol. 15, Issue 8
  • DOI: 10.1038/nri3859

Decade-long bacterial community dynamics in cystic fibrosis airways
journal, March 2012

  • Zhao, J.; Schloss, P. D.; Kalikin, L. M.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 15
  • DOI: 10.1073/pnas.1120577109

The opportunistic pathogen Pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase
journal, February 2004

  • Vance, Russell E.; Hong, Song; Gronert, Karsten
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 7
  • DOI: 10.1073/pnas.0307308101

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925