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Environmental adaptation by Vibrio cholerae

霍乱弧菌的环境适应

基本信息

批准号：
10656646
负责人：
JAMES Edward BINA
金额：
$ 27.92万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-03 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656646
关键词：
Acute Diarrhea Address Adherence Affect Cell Density Cell division Cells Cholera Consumption Cues Dehydration Development Diarrhea Disease Down-Regulation Drug Efflux Ecosystem Epidemic Feedback Food Gene Expression Gene Expression Regulation Genes Genetic Transcription Gram-Negative Bacteria Growth Human Impairment In Vitro Infection Ingestion Intestines Iron Life Cycle Stages Link Mediating Metabolism Microbial Biofilms Modeling Paper Pathogenesis Persons Phenotype Process Production Proteins Regulon Repression Research Resistance Resistance to infection Signal Transduction Signaling Molecule Small Intestines System Testing Toxin Up-Regulation VAI-2 Vibrio cholerae Virulence Virulence Factors aquatic organism bile salts combat contaminated water diarrheal disease environmental adaptation human disease human pathogen in vivo Model mutant novel novel strategies novel therapeutic intervention pathogen periplasm purge quorum sensing response sensor transmission process virulence gene

项目摘要

PROJECT SUMMARY/ABSTRACT Cholera is an acute diarrheal disease that affects 3-5 million people each year. Cholera is an is caused by the Gram negative bacterium Vibrio cholerae and is frequently associated with epidemic disease. V. cholerae is a native to aquatic ecosystems and a facultative human pathogen that infects people through the consumption of contaminated water or food. Once ingested, V. cholerae colonizes the small intestine where it produces a toxin that causes a dehydrating secretory diarrhea that can be rapidly fatal. The devastating consequences of cholera, combined with the rapidity with which it can spread and its ability to persist in aquatic ecosystems, underscore the need for the development of novel approaches to combat this epidemic disease. Our recent studies in V. cholerae documented that multiple drug efflux systems belonging to the resistance-nodulation-division (RND) superfamily function to efflux cellular metabolites from the cell. We further showed that impaired efflux resulted in the metabolites accumulating intracellularly where they interacted with periplasmic sensor proteins to initiate adaptive responses. This included the activation of ToxR which resulted in increased leuO transcription and the downregulation of virulence gene expression. However, the metabolites that were responsible for virulence repression remain unknown. In this proposal we will test the hypothesis that auto-inducers function to initiate the expression of the adaptive responses that resulted in virulence repression. Two specific aims are proposed. The first aim will investigate the function of ToxR and LeuO in cell density-dependent gene regulation. The second aim will investigate the contribution of RND-mediated efflux to adaptive responses and colonization. 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 disease and epidemic spread, and highlight novel approaches to combat cholera.

项目总结/文摘