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Edited by Christopher L. Karp, Bill & Melinda Gates Foundation, and accepted by Editorial Board Member Ruslan Medzhitov November 22, 2016 (received for review June 28, 2016)
Significance
Pseudomonas aeruginosa pulmonary infections cause prolonged and destructive inflammation for cystic fibrosis patients. Despite vigorous neutrophilic responses, P. aeruginosa persists in a chronic hyperinflammatory environment. We show that the P. aeruginosa virulence factor, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), promotes sustained airway inflammation by reducing host pro-resolving lipid mediators. Cif hydrolyzes epithelial-derived 14,15-epoxyeicosatrienoic acid, disrupting transcellular production of the proresolving lipid 15-epi lipoxin A4 (15-epi LXA4) by neutrophils. Clinical data from cystic fibrosis patients revealed that Cif abundance correlated with increased inflammation, decreased 15-epi LXA4, and reduced pulmonary function. Our study and the recent identification of Cif homologs in Acinetobacter and Burkholderia species suggest that bacterial epoxide hydrolases represent a novel virulence strategy shared by multiple respiratory pathogens.
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.
Footnotes
↵1B.A.F. and K.L.H. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: jbomb{at}pitt.edu or drm0001{at}dartmouth.edu.
Author contributions: B.A.F., K.L.H., C.M., B.D.H., J.S.L., J.K.K., B.D.L., D.R.M., and J.M.B. designed research; B.A.F., K.L.H., E.O., T.E., J.Y., D.H.K., C.D.B., and J.M.B. performed research; X.L., J.S.L., and J.K.K. contributed new reagents/analytic tools; B.A.F., K.L.H., E.O., T.E., J.Y., D.H.K., C.D.B., T.H.H., J.K.K., B.D.L., D.R.M., and J.M.B. analyzed data; and B.A.F., K.L.H., C.M., B.D.H., J.S.L., J.K.K., B.D.L., D.R.M., and J.M.B. wrote the paper.
Conflict of interest statement: C.D.B., C.M., B.D.H., and D.R.M. are coinventors of patent-pending Cif inhibitor compounds. B.D.L. is an inventor on patents (resolvins) licensed by Brigham and Women’s Hospital to Resolvyx Pharmaceuticals, a company that seeks to develop Resolvin therapeutics for inflammatory diseases. B.D.L. also owns equity in the company. B.D.L.’s interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.
This article is a PNAS Direct Submission. C.L.K. is a Guest Editor invited by the Editorial Board.
Data deposition: For the crystallographic structure reported in this paper, atomic coordinates and structure factors have been deposited in the Protein Data Bank (PDB), www.pdb.org (PDB ID code 5JYC).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1610242114/-/DCSupplemental.
Cif reduces 15-epi lipoxin A4 function in the lung
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