Mechanisms of Clostridium difficile spore germination

艰难梭菌孢子萌发机制

基本信息

批准号：
10595513
负责人：
Joe Sorg
金额：
$ 44.05万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595513
关键词：
Air Alleles Amino Acids Anaerobic Bacteria Antibiotic Resistance Antibiotics Appearance Bacillus subtilis Bacteria Bile Acids Binding Biological Assay Cell Wall Cells Chenodeoxycholic Acid Clostridium difficile Complex Data Disease Dissociation Dryness Endospore-Forming Bacteria Environment Epidemic Excretory function Exposure to Gastrointestinal tract structure Genes Genetic Screening Germ Cells Germination Glycine Growth Healthcare Systems Hospitals Immunocompromised Host Immunoprecipitation Incubated Infection Knowledge LytA enzyme Mediating Membrane Molecular Molecular Target Morbidity - disease rate Mothers Mutagenesis Mutate Organism Pathogenesis Pathway interactions Patients Peptide Hydrolases Phase Phenotype Process Production Protein Secretion Proteins Reaction Recombinants Reporting Reproduction spores Research Personnel Risk Role Signal Transduction Signaling Protein Site Surface Symptoms Taurocholic Acid Testing Toxin United States Work antibiotic-associated diarrhea candidate validation combat cost cost estimate design endolysin experimental study health care settings hybrid protein inhibitor mortality mouse model mutant novel novel therapeutics protein purification receptor validation studies

项目摘要

Clostridium difficile is the leading cause of antibiotic-associated diarrhea in the hospital and long term health care settings. In addition to the patient toll, the treatment-associated costs of C. difficile infections to the United States healthcare system have been estimated at $5 billion. Although the rate of C. difficile infection in the United States is rising, surprisingly little is known about the mechanisms of C. difficile pathogenesis. C. difficile is believed to be acquired by the host in the form of a dormant spore. To cause disease, the spore must respond in the gastrointestinal tract to signals that trigger germination, thereby allowing growth as a vegetative bacterium, toxin production and subsequent spore formation before excretion into the environment. Taurocholic acid, a bile acid normally found in the GI tract, and glycine are co- germinants for C. difficile spores. Another bile acid, chenodeoxycholic acid, inhibits taurocholic acid-mediated germination and is toxic for C. difficile vegetative growth. In prior work, the molecular target of bile acids on the C. difficile spore was identified - identifying the first C. difficile spore germinant receptor. This led to the finding that C. difficile spore germination proceeds through a novel, ‘outside – in’ germination pathway. More recently, the target of the amino acid co-germinants on the C. difficile spore was identified. In this proposal, the investigator proposes to: (1) characterize how the C. difficile ‘germinosome’ proteins interact; (2) define the mechanism of localization of these proteins in the C. difficile spore; (3) globally identify YabG protease targets; and (4) characterize the impact of these targets on C. difficile pathogenesis. Successful completion of the experiments outlined herein will extend the understanding of the mechanisms of C. difficile germination, open new avenues in the study of C. difficile spore formation and spore germination.

艰难梭菌是医院与抗生素相关腹泻的主要原因，很长任期医疗保健设置。除了患者损失外，与治疗相关的成本C。美国医疗体系的艰难梭菌感染估计为50亿美元。尽管美国艰难梭菌感染的速度正在上升，但令人惊讶的是鲜为人知关于艰难梭菌发病机理的机制。艰难梭菌被认为是由以休眠酱的形式寄主。要引起疾病，孢子必须在胃肠道到引发发芽的信号，从而成为蔬菜的生长细菌，毒素产生和随后的散射形成，然后排泄到环境。牛胆酸，一种通常在胃肠道中发现的胆汁酸，甘氨酸是共同的艰难梭菌孢子的发芽剂。另一个胆汁酸Chendoxycholic抑制牛螺果酸介导的发芽，对艰难梭菌营养生长有毒。在先前的工作中鉴定出胆汁酸在艰难梭菌酱上的分子靶标 - 鉴定出第一个C. 艰难的孢子发芽受体。这导致发现艰难梭菌孢子发芽通过小说“外部 - 在”发芽途径进行。最近，鉴定出艰难梭菌酱上的氨基酸共晶。在此提案中，研究者提出的建议：（1）表征艰难梭菌的“生殖体”蛋白如何相互作用；（2）定义这些蛋白质在艰难梭菌孢子中的定位机制；（3）全球识别YABG蛋白酶靶标；（4）表征这些目标对艰难梭菌的影响发病。成功完成此处概述的实验将扩展了解艰难梭菌发芽的机制，开放的新途径艰难梭菌酱形成和酱汁发芽。