Cholera is an acute diarrheal disease that is caused by Vibrio cholerae. V. cholerae is a Gram- negative bacterium and facultative human pathogen that is native to aquatic ecosystems around the world. The worldwide distribution of V. cholerae makes it a significant health threat anytime human populations lack access to clean water; a fact exemplified by the ongoing cholera epidemic in Yemen. The devastating consequences of cholera combined with its ability to persist in the environment have accentuated the need for new therapeutic approaches to limit the epidemic spread of this disease. We recently discovered that RND-mediated efflux is linked to V. cholerae adaptive responses. In the absence of RND-mediated efflux unknown cell metabolites accumulate in V. cholerae can serve as cues to repress V. cholerae virulence. The overarching goal of this proposal is to identify these metabolites and characterize the role of the V. cholerae RND transporters in their efflux.
Two specific aims are proposed.
The first aim will identify the metabolites that are substrates of the RND efflux systems.
The second aim will identify regulators of the RND efflux systems and determine how the metabolites affect the expression of the RND systems. Determining the regulatory mechanisms and environmental cues that modulate V. cholerae adaptive responses will illuminate important aspects of V. cholerae pathogenesis, provide a better understanding of the factors that contribute to epidemic spread, and may lead to the development of novel approaches to combat the disease cholera.

Public Health Relevance

. Vibrio cholerae is a gram negative bacterium and facultative human pathogen that causes the acute diarrheal disease cholera. Cholera is an epidemic disease that is estimated to affect 3-5 million people each year, but has been expanding in many regions of the world. The research proposed in this project is focused on identifying metabolites that could be used in the development of new therapeutic approaches to limit the epidemic spread of cholera.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI141934-01
Application #
9648289
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hall, Robert H
Project Start
2018-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213