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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.

艰难梭菌是医院和长年抗生素相关性腹泻的主要原因定期保健设置。除了患者的费用外，与C。据估计，美国医疗系统感染艰难梭菌的金额为50亿美元。尽管艰难梭菌在美国的感染率正在上升，但令人惊讶的是，人们对此知之甚少艰难梭菌致病机制的研究。艰难梭菌被认为是由以休眠孢子的形式寄主。为了致病，孢子必须对胃肠道触发萌发的信号，从而允许作为植物人生长细菌、毒素产生和随后的孢子形成，然后排泄到环境。牛磺胆酸，一种通常在胃肠道中发现的胆汁酸，和甘氨酸是共同的艰难梭菌孢子的萌发剂。另一种胆汁酸，鹅去氧胆酸，抑制牛磺胆酸酸介导的萌发，对艰难梭菌的营养生长是有毒的。在以前的工作中，确定了艰难梭菌孢子上胆汁酸的分子靶点--鉴定了第一株艰难梭菌。艰难梭菌孢子萌发受体。这导致发现艰难梭菌的孢子萌发通过一种新颖的“由外而内”的萌发途径进行。最近，美国政府的目标鉴定了艰难梭菌孢子上的氨基酸共萌发菌。在这项提案中，研究人员建议：(1)描述艰难梭菌‘生殖小体’蛋白如何相互作用；(2) 确定这些蛋白质在艰难梭菌孢子中定位的机制；(3)全球确定YabG蛋白酶靶标；以及(4)表征这些靶标对艰难梭菌的影响发病机制。本文概述的实验的成功完成将延长了解艰难梭菌的萌发机制，为研究艰难梭菌开辟新的途径艰难梭菌孢子形成和孢子萌发。