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

艰难梭状芽胞杆菌感染(CDI)仍然是医疗保健相关感染的最常见原因，尽管各方共同努力减少这种感染的发生率。越来越多的艰难梭菌在社区中发现，最近没有接触过医疗保健的人。该项目的长期目标是确定可用于治疗CDI和控制艰难梭菌传播的新的治疗靶点。本应用的总体目标是(I)阐明艰难梭菌正选择下糖转运蛋白的特异性和冗余性，(Ii)确定它们在疾病中的作用，以及(Iii)检查饮食中糖对无症状携带的影响。中心假设是艰难梭菌通过利用现代富含糖分的饮食，进化成更好地占据胃肠道(GIT)内的生态位空间。这个项目的基本原理是，确定艰难梭菌携带和感染过程中糖转运体和下游代谢的特异性和重要性，建立一个强有力的科学框架，从而可以开发新的预防和治疗策略。中心假设将通过追求三个具体目标来验证：1)阐明进化糖运输基因的特异性、冗余性及其对毒素产生的影响，2)确定进化糖运输基因对群落入侵和疾病的影响，以及3)调查糖在生态位建立和无症状携带中的作用。本申请中提出的研究具有创新性，因为它侧重于艰难梭菌对碳水化合物的代谢适应及其在无症状携带和疾病中的作用。这一重点有可能导致新的预防策略，可用于在艰难梭菌出现之前对其进行预防。这项拟议的研究具有重要意义，因为它将为继续研究艰难梭菌的代谢作为毒力机制提供坚实的科学依据，并为未来新的预防、干预和治疗方案的研究提供一个框架。

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 modem 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. 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.