Flitter, Becca
(2017)
HOST PATHOGEN INTERACTIONS IN THE CYSTIC FIBROSIS AIRWAY: PSEUDOMONAS AERUGINOSA IMPAIRS THE RESOLUTION OF PULMONARY INFLAMMATION BY MANIPULATING HOST LIPID SIGNALING.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Pseudomonas aeruginosa is a clinically important, opportunistic bacterial pathogen that can cause a wide range of severe infections. The bacterium is inherently resistant to many antibiotics and chronic infections are very difficult to treat. Patients with the genetic disease cystic fibrosis (CF) often have recurrent P. aeruginosa pulmonary infections resulting in robust inflammatory responses that lead to tissue destruction. Despite a hostile hyper-inflammatory environment and vigorous neutrophilic responses, P. aeruginosa can persist in the CF lung and eventually become the dominant bacterium in the airways.
We demonstrate that P. aeruginosa manipulates host lipid signaling and inflammatory response in the CF airway by secreting Cif, a virulence factor with epoxide hydrolase activity. Cif reduced the transcellular production of 15-epi lipoxin A4 (15-epi LXA4), a pro-resolving lipid mediator whose endogenous production is critical in limiting tissue inflammation. In the airway, neutrophil 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotaged the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating neutrophil generation of 15-epi LXA4. Cif mediated inhibition of 15-epi LXA4 eliminated the pro-resolving signal that potently suppresses IL-8-driven neutrophil trans-epithelial migration in vitro. Moreover, our retrospective analyses of CF patient samples supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations and impaired lung function. These findings provide structural, biochemical and immunological evidence that the P. aeruginosa epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections in the CF airway. This 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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
31 January 2017 |
| Date Type: |
Publication |
| Defense Date: |
17 November 2016 |
| Approval Date: |
31 January 2017 |
| Submission Date: |
12 December 2016 |
| Access Restriction: |
3 year -- Restrict access to University of Pittsburgh for a period of 3 years. |
| Number of Pages: |
121 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Pseudomonas aeruginosa, inflammation, bacterial epoxide hydrolase, cystic fibrosis |
| Date Deposited: |
31 Jan 2017 20:20 |
| Last Modified: |
31 Jan 2020 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30852 |
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