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Phase variation of virulence factors in Clostridium difficile

艰难梭菌毒力因子的相位变化

基本信息

批准号：
10231056
负责人：
RITA TAMAYO
金额：
$ 41.55万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231056
关键词：
5&apos Untranslated Regions Adherence Affect Anabolism Animal Disease Models Animal Model Antibiotics Area Attenuated Bacteria Binding Sites Biochemistry Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Clostridium difficile Code Cytotoxin DNA DNA Sequence Data Development Diarrhea Disease Down-Regulation Epithelial Cells Flagella Gene Expression Gene Expression Regulation Genes Genetic Recombination Genetic Transcription Goals Health Care Costs Human Immune In Vitro Infection Inflammatory Response Intestines Investigation Knowledge Laboratories Link Mediating Messenger RNA Mission Modeling Molecular Molecular Biology Operon Pathogenesis Pathogenicity Phase Physiological Physiological Processes Physiology Preventive Production Pseudomembranous Colitis Public Health Publishing Regulation Regulatory Element Reporting Research Resources Rho Factor Role Sigma Factor Site Swimming Symptoms Testing Therapeutic Toxin Transcript Transcription Initiation United States National Institutes of Health Variant Virulence Virulence Factors bacterial genetics base cell motility combat gene product gut colonization host colonization in vivo innovation intestinal epithelium mutant pathogen pathogenic bacteria premature recombinase rho transcription termination

项目摘要

PROJECT SUMMARY Clostridium difficile is a major public health threat, causing disease ranging from mild diarrhea to pseudomembranous colitis. C. difficile disease symptoms are largely mediated by the secreted cytotoxins, TcdA and TcdB. Many aspects of the pathogenicity of this bacterium remains poorly understood, including how C. difficile regulates the production of the toxins and other virulence factors. Toxin gene expression is linked to expression of flagellar genes via the flagellar sigma factor sigma-D, which is encoded in the flgB operon. Thus, factors that regulate the expression of the flgB operon will impact toxin production in addition to flagellar motility. Our long-term goal is to determine how C. difficile coordinately regulates flagellum and toxin gene expression, as these mechanisms are likely fundamental to pathogenesis. We recently showed that flagellar gene expression is subject to phase variation through site-specific DNA recombination of an invertible sequence upstream of the flgB operon. Notably, inversion of the DNA sequence, which we term the “flagellar switch”, also impacts the production of toxins essential for virulence. We identified RecV as the DNA recombinase that mediates inversion of the flagellar switch, and we have begun to define the mechanism by which the orientation of the flagellar switch sequence controls gene expression. Our central hypothesis is that phase variation of flagellum and toxin production is critical to C. difficile pathogenesis, and consequently interfering with the ability of C. difficile to phase vary will attenuate one or more aspects of virulence. While flagella and/or motility may be important for some aspects of infection, downregulation of flagella is likely vital for C. difficile to evade host immune recognition. Toxin production may similarly be beneficial or detrimental to C. difficile during different stages of infection. The objective of this proposal is to define the molecular mechanisms underlying phase variation and to evaluate the impact of phase variation on host colonization and virulence. This proposal is innovative because it represents an entirely new area of investigation toward understanding C. difficile disease: phase variable expression of flagella and toxins. Completion of the proposed studies will provide much needed mechanistic information on how C. difficile controls virulence factor production during infection, and may expose potential targets for inhibition of intestinal colonization and toxin production to facilitate efforts to combat this increasingly problematic pathogen.

项目总结