Taylor, Dawn L.
(2014)
Characterization of the Vibrio cholerae RND efflux systems.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The resistance-nodulation-division (RND) family efflux systems are ubiquitous transporters that have been extensively studied due to their ability to efflux a broad range of xenobiotic substrates. There is increasing evidence to suggest that the RND efflux systems have physiological roles beyond xenobiotic resistance to include pathogenesis and cellular stress responses. The Vibrio cholerae genome encoded six RND efflux systems: VexAB, VexCD, VexEF, VexGH, VexIJK, and VexLM. This work sought to characterize the role of these systems in antimicrobial resistance, pathogenesis, and environmental stress.
The V. cholerae RND efflux systems were characterized according to their substrate specificity and contribution to antimicrobial resistance. The VexAB, VexCD, VexGH, and VexIJK RND efflux systems were shown to contribute to resistance against multiple antibiotics, bile salts, and other detergents. In addition to functioning in antimicrobial resistance, the RND efflux systems were found to function in the extrusion of metabolic intermediates. In the absence of RND efflux, the accumulation of potentially toxic metabolites induced the expression of vexRAB, vexGH, and the Cpx membrane stress response system. Subsequent studies showed that independent activation of the Cpx system also resulted in the induction of vexRAB and vexGH expression, which indicated that the Cpx system and the vexRAB and vexGH RND efflux systems were reciprocally regulated. Collectively these results suggested a model whereby the vexRAB and vexGH RND efflux systems function to reduce cellular stress resulting from endogenous metabolites, xenobiotics, and factors that induce a membrane stress response.
The VexAB RND system was also found to be positively regulated by VexR, a TetR-family regulator that was encoded within the same operon (i.e. vexRAB). VexR activated vexRAB expression in response to VexAB efflux substrates and in the absence of RND efflux activity. The latter phenotype suggested that the VexR modulated vexRAB expression in response to endogenous cues. Overall the data presented in this thesis supported the conclusion that the V. cholerae RND efflux systems functioned in responses that were essential for environmental adaptation including intestinal colonization, xenobiotic resistance, metabolic imbalance, and membrane stress.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
20 August 2014 |
| Date Type: |
Publication |
| Defense Date: |
8 August 2014 |
| Approval Date: |
20 August 2014 |
| Submission Date: |
20 August 2014 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
181 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Vibrio cholerae, RND efflux systems, TetR regulator, Cpx system, indole, cholera toxin |
| Date Deposited: |
20 Aug 2014 15:44 |
| Last Modified: |
20 Aug 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/22786 |
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