Environmental adaptation by Vibrio cholerae

霍乱弧菌的环境适应

• 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
• 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

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.

项目概要/摘要 霍乱是一种急性腹泻病，每年影响 3-500 万人。霍乱是一种 由革兰氏阴性菌霍乱弧菌引起，通常与流行病有关 疾病。霍乱弧菌是水生生态系统的原生生物，也是一种兼性人类病原体，可感染 人们通过饮用受污染的水或食物。一旦被摄入，霍乱弧菌就会在体内定殖 小肠产生一种毒素，导致脱水性分泌性腹泻，这种腹泻可以迅速发生 致命的。霍乱造成的毁灭性后果，加上其传播速度之快， 它在水生生态系统中持续存在的能力，强调了开发新方法的必要性 来对抗这种流行病。我们最近对霍乱弧菌的研究表明，多种药物外流 属于抵抗结节分裂（RND）超家族的系统，具有流出细胞的功能 来自细胞的代谢物。我们进一步表明，外排受损导致代谢物积累 在细胞内，它们与周质传感器蛋白相互作用以启动适应性反应。这 包括 ToxR 的激活，导致 leuO 转录增加和 leuO 转录下调 毒力基因表达。然而，负责毒力抑制的代谢物 仍然未知。在本提案中，我们将测试自诱导器功能启动的假设 导致毒力抑制的适应性反应的表达。两个具体目标是 建议的。第一个目标是研究ToxR和LeuO在细胞密度依赖性基因中的功能 规定。第二个目标是研究 RND 介导的外流对适应性反应的贡献 和殖民。确定调节 V 的调节机制和环境线索。 霍乱弧菌适应性反应将阐明霍乱弧菌发病机制的重要方面，提供 更好地了解导致疾病和流行病传播的因素，并突出新的 防治霍乱的方法。