Howard, Mondraya
(2019)
ToxR Regulation of Adaptive Responses in Vibrio cholerae.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Vibrio cholerae is the causative agent of the acute diarrheal disease cholera. Cholera is a major public health risk in regions lacking access to safe drinking water and adequate sanitation. There are an estimated 1-4 million annual cases of cholera worldwide. V. cholerae has a unique life cycle where it inhabits two distinct environments, aquatic ecosystems and the human intestine. The success of V. cholerae as a pathogen stems from its ability to rapidly alter its gene expression in response to environmental signals to survive, colonize and proliferate in the small intestine and subsequently disseminate into the aquatic environment. The V. cholerae infection cycle is composed of two stages. In early infection, V. cholerae must overcome a variety of host defenses to produce virulence factors that facilitate intestinal colonization and disease development. In late infection, V. cholerae replicates to high cell density and prepares to leave the human host by turning off virulence genes and inducing expression of genes that enhance environmental fitness or infectivity of V. cholerae for transmission to new hosts. The membrane bound transcription factor and environmental sensor ToxR is critical for V. cholerae pathogenesis. ToxR has been extensively studied for its role in early infection. ToxR is the activator of virulence gene expression and mediates stress responses including bile resistance, acid tolerance and antimicrobial peptide resistance. In this work, we sought to characterize the role of ToxR in environmental adaptation. We have shown that the functional role of ToxR in antimicrobial resistance extends to cell surface remodeling and cationic antimicrobial resistance. Furthermore, we found that ToxR likely functions at late infection to repress virulence in response to cell metabolites. Our collective results suggest a model where ToxR contributes to spatial and temporal regulation of adaptive responses through the host gastrointestinal tract. In this model we propose ToxR integrates host-derived environmental cues to overcome antimicrobial challenge and facilitate virulence gene expression. In late infection, ToxR senses and responds to bacterial-derived cell metabolites to regulate phenotypes, including virulence repression that prepare V. cholerae for dissemination.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
2 July 2019 |
| Date Type: |
Publication |
| Defense Date: |
11 April 2019 |
| Approval Date: |
2 July 2019 |
| Submission Date: |
13 June 2019 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
130 |
| 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, ToxR, LeuO, virulence regulation |
| Date Deposited: |
02 Jul 2019 14:05 |
| Last Modified: |
02 Jul 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36933 |
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