The role of sugar transport in C. difficile colonization and disease

糖转运在艰难梭菌定植和疾病中的作用

• 批准号: 10492100
• 负责人: James Tristan Collins
• 金额: $ 27.39万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10492100
• 关键词: Accounting; Adult; Antibiotics; Biological Assay; Bioreactors; Carbohydrates; Clostridium difficile; Communities; Data; Development; Diet; Dietary Sugars; Disease; Enabling Factors; Environment; Environmental Risk Factor; Epidemic; Future; Gastrointestinal tract structure; Genes; Goals; Growth; Healthcare; Horizontal Disease Transmission; Hospitalization; Hospitals; Human; In Vitro; Incidence; Infection; Inflammation; Intake; Intervention; Intestines; Invaded; Link; Metabolic; Metabolism; Modeling; Modernization; Mouse Strains; Nutrient; Nutrient availability; Organism; Outcome; Pathogenicity; Persons; Population; Process; Production; Prophylactic treatment; Research; Role; Severity of illness; Shapes; Solid; Specificity; System; Testing; Toxic effect; Toxin; Trehalose; Virulence; Work; colonization resistance; dysbiosis; evidence base; gut microbiota; healthcare-associated infections; host microbiota; human old age (65+); innovation; insight; microbiome research; microbiota; mouse model; new therapeutic target; novel; pathogen; prevent; prophylactic; sugar; treatment strategy

Project Summary/Abstract Clostridioides difficile infection (CDI) is still the most common cause of healthcare-associated infection despite a concerted effort to reduce the incidence. Increasingly, C. difficile is found in the community among persons with no recent healthcare contact. The long-term goal of this project is to identify novel therapeutic targets which can be exploited to treat CDI and control the spread of C. difficile. The overall objectives in this application are to (i) elucidate the specificity and redundancy of the sugar transporters under positive selection in C. difficile, (ii) determine their role in disease, and iii) examine the impact of dietary sugar on asymptomatic carriage. The central hypothesis is that C. difficile has evolved to better occupy niche space within the gastrointestinal tract (GIT) by taking advantage of the modern sugar-rich diet. The rationale for this project is that determining the specificity and importance of sugar transporters and downstream metabolism in C. difficile carriage and infection sets up a robust scientific framework whereby new prophylaxis and treatment strategies can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Elucidate the specificity, redundancy, and influence on toxin production of evolving sugar transport genes, 2) Determine the effect of evolving sugar transport genes on community invasion and disease, and 3) Investigate the role of sugars in niche establishment and asymptomatic carriage. Under the first aim, clean deletions of sugar transporters previously shown to be under positive selection in epidemic C. difficile will be generated and their effect on growth and toxin production assessed. The second aim will determine the role of sugar transport in invasion using a novel in vitro bioreactor assay and disease by utilizing a mouse model of CDI. Finally, aim three will assess the role of sugar availability in asymptomatic C. difficile colonization by using toxin negative C. difficile strains and a novel 13 strain mouse microbiota colonization model. The research proposed in this application is innovative, because it focuses on the metabolic adaptation of C. difficile to carbohydrates and their role in asymptomatic carriage as well as disease. This focus has the potential to lead to novel prophylactic strategies that can be used against C. difficile before the emergence of the disease. The proposed research is significant as it will provide a solid scientific justification for the continued examination of metabolism as a virulence mechanism in C. difficile and provide a framework for the future study of novel prophylactic, intervention, and treatment options.

项目总结/摘要 艰难梭菌感染（CDI）仍然是医疗保健相关感染的最常见原因， 共同努力降低发病率。越来越多，C。difficile是在社区中发现的， 最近没有接触过医护人员该项目的长期目标是确定新的治疗靶点， 可用于治疗CDI和控制C.很难本申请的总体目标是 （i）阐明在正选择条件下，C. difficile，（ii） 确定它们在疾病中的作用，和iii）检查饮食糖对无症状携带的影响。的 中心假设是C.艰难梭菌已经进化到更好地占据胃肠道内的小生境空间 (GIT)通过利用现代高糖饮食。该项目的基本原理是， 糖转运蛋白和下游代谢的特异性和重要性。艰难梭菌携带和感染 建立了一个强大的科学框架，从而可以开发新的预防和治疗策略。的 中心假设将通过追求三个具体目标进行测试：1）阐明特异性，冗余， 对进化糖转运基因的毒素产生的影响，2）确定进化糖转运基因对毒素产生的影响。 3）研究糖在生态位建立中的作用 和无症状携带在第一个目标下，先前显示的糖转运蛋白的干净缺失是 在流行病C的正选择下。将产生艰难梭菌及其对生长和毒素产生的影响 评估。第二个目标将使用一种新的体外生物反应器确定糖转运在入侵中的作用 通过利用CDI的小鼠模型来进行测定和疾病。最后，目标三将评估糖供应的作用 无症状C.艰难梭菌的定殖。difficile菌株和一种新的13品系小鼠 微生物定植模型本申请中提出的研究是创新的，因为它侧重于 C.碳水化合物及其在无症状携带中的作用， 疾病这一焦点有可能导致新的预防策略，可用于对C。艰难 在疾病出现之前。这项拟议中的研究意义重大，因为它将提供一个坚实的科学基础。 继续研究代谢作为C. difficile并提供一个 新的预防，干预和治疗方案的未来研究的框架。