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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.

艰难梭菌是医院抗生素相关性腹泻的主要原因，长期以来术语医疗保健机构。除了患者死亡人数外，与治疗相关的费用 C. 据估计，艰难梭菌感染给美国医疗保健系统带来了 50 亿美元的损失。尽管美国的艰难梭菌感染率正在上升，但令人惊讶的是我们对此知之甚少关于艰难梭菌发病机制。艰难梭菌被认为是由宿主以休眠孢子的形式存在。为了引起疾病，孢子必须在胃肠道发出触发发芽的信号，从而允许植物生长细菌、毒素产生以及随后的孢子形成，然后排泄到环境。牛磺胆酸（一种通常存在于胃肠道中的胆汁酸）和甘氨酸共同作用艰难梭菌孢子的萌芽体。另一种胆汁酸，鹅去氧胆酸，抑制牛磺胆酸酸介导的发芽，对艰难梭菌营养生长有毒。在之前的工作中，确定了艰难梭菌孢子上胆汁酸的分子靶点 - 确定了第一个艰难梭菌。艰难梭菌孢子萌发受体。这导致发现艰难梭菌孢子萌发通过一种新颖的“从外到内”的萌芽途径进行。最近，目标是鉴定出艰难梭菌孢子上的氨基酸共萌芽体。在该提案中，研究人员建议：（1）描述艰难梭菌“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) 全球范围确定 YabG 蛋白酶靶标； (4) 描述这些目标对艰难梭菌的影响发病。成功完成本文概述的实验将扩展了解艰难梭菌萌发机制，为研究开辟新途径艰难梭菌孢子形成和孢子萌发。