Host-induced Initiation of Clostridium difficile Sporulation

宿主诱导艰难梭菌孢子形成的启动

• 批准号: 9088329
• 负责人: SHONNA M. MCBRIDE
• 金额: $ 38.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088329
• 关键词: Alcohols; Anaerobic Bacteria; Antibiotic Resistance; Antibiotic Therapy; Bacillus subtilis; Bacteria; Bacterial Infections; Cells; Cessation of life; Clostridium difficile; Cues; Data; Defect; Development; Digestive System Disorders; Disease; Disinfectants; Environment; Ethanolamines; Exposure to; Feces; Frequencies; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Germination; Goals; Growth; Health; Health Care Costs; In Vitro; Individual; Infection; Ingestion; Intestinal Diseases; Intestines; Life Cycle Stages; Link; Mediating; Metabolic; Metabolism; Mission; Modeling; Molecular; Molecular Genetics; Mutagenesis; Nutrient; Nutritional; Oral; Pathogenesis; Pathway interactions; Production; Recurrence; Refractory; Regulation; Regulator Genes; Relapse; Reproduction spores; Research; Resistance; Role; Route; Signal Transduction; Staging; Stimulus; System; Time; Toxin; base; bile salts; design; experience; genetic analysis; genetic regulatory protein; genome analysis; in vivo; innovation; meetings; mutant; particle; pathogen; prevent; research study; response; transmission process

 DESCRIPTION (provided by applicant): Clostridium difficile is a major nosocomial pathogen that causes severe diarrheal disease that is highly infectious and difficult to treat. C. difficileis easily transmitted due to the formation and expulsion of contagious spores from infected hosts. The spore form of C. difficile is resistant to most disinfectants and is critical for the survival f the bacterium outside of the host. The only natural environment known to support C. difficile spore formation is the gastrointestinal tract, yet we know very little about how spore formation occurs. We hypothesize that sporulation of C. difficile is initiated in response to signals found within the host intestine, through unknown and unique genetic mechanisms. The long-term goal of this project is to uncover the intestinal environment triggers C. difficile sporulation. The specific objectives of this application are to identify the genetic mechanisms required for spore initiation and determine how sporulation is initiated in the host. Capitalizing on our previous experience with Bacillus subtilis sporulation, Gram-positive intestinal pathogenesis and C. difficile molecular genetics, we will meet these objectives through the experiments detailed in two specific aims. First, we will reveal the genetic mechanisms of spore initiation in C. difficile through genetic analysis of sporulation-defective mutants and newly identified early sporulation regulators. In parallel, we will evaluate the effects of identified and suspected sporulation-inducing compounds on the timing and frequency of spore formation. The research proposed in this application is innovative because it represents a departure from the model sporulation paradigm as the archetypal standard for spore initiation by C. difficile and seeks to uncover the unique mechanisms that regulate sporulation in this pathogen. The expected contribution of the proposed research is a detailed understanding of the genes required for spore initiation and the development of spores within the host. This contribution is significant because it is the first ste in the development of strategies to prevent spore formation by C. difficile.

 描述（由申请人提供）：艰难梭菌是一种主要的医院病原体，可引起严重的呼吸道疾病，具有高度传染性，难以治疗。艰难梭菌很容易传播，这是由于感染的宿主形成并排出具有传染性的孢子。C.艰难梭菌对大多数消毒剂具有抗性，并且对于细菌在宿主外的存活至关重要。目前已知的唯一支持C.艰难梭菌孢子的形成是在胃肠道，但我们对孢子的形成知之甚少。我们推测C.艰难梭菌通过未知和独特的遗传机制响应宿主肠道内发现的信号而启动。本项目的长期目标是揭示肠道环境触发C。艰难孢子形成。本申请的具体目的是确定孢子起始所需的遗传机制，并确定孢子形成是如何在宿主中起始的。利用我们以前的经验，枯草芽孢杆菌孢子形成，革兰氏阳性肠致病和C。困难的分子遗传学，我们将满足这些目标，通过实验中详细介绍了两个具体目标。首先，我们将揭示C.艰难 通过对孢子形成缺陷突变体和新鉴定的早期孢子形成调节剂的遗传分析。同时，我们将评估鉴定和疑似孢子形成诱导化合物对孢子形成时间和频率的影响。本申请中提出的研究是创新性的，因为它代表了对作为C. difficile并试图揭示调节这种病原体孢子形成的独特机制。拟议研究的预期贡献是详细了解孢子启动和孢子在宿主内发育所需的基因。这一贡献是重要的，因为它是第一步，在发展战略，以防止孢子形成的C。很难