Aging and Clostridium difficile infection: interplay of microbiota and host response

项目摘要/摘要 意义：艰难梭菌是引起医疗保健相关感染的最常见病原体， 已导致腹泻疾病成为美国传染病死亡率上升的唯一原因 从2000年到2014年。65岁或65岁以上的成年人不仅更有可能被感染，而且他们占死亡人数的90% 艰难梭菌感染(CDI)。研究增加死亡和严重疾病风险的机制 CDI在老年宿主中的结果现在比以往任何时候都更加重要。 方法：我们的初步研究表明，老年小鼠的早期先天免疫反应较低，而较高 CDI的死亡率，但随着年龄的增长，死亡率和免疫反应的这些差异可以通过 从幼年小鼠到老年小鼠的粪便微生物群移植。使用一种新的CDI衰老小鼠模型 发展起来，我将找出调节衰老小鼠肠道保护的因素 微生物组/代谢组方(目标1)和宿主反应方(目标2)。目标1将分析微生物组 和代谢组，以识别保护性细菌和代谢物，以测试对老年小鼠CDI的保护作用。 AIM 2将利用RNA测序和流式细胞术来识别免疫细胞和介导 微生物群对宿主反应的影响，并在粪便移植实验中通过逆转途径来测试它们。 结合这两个目标的发现将使我们能够更全面地描述发病机制并发现 开发新疗法的目标。 职业发展：这项提议充分利用了机构承诺和培训环境 弗吉尼亚大学，沃伦/格伦特实验室的资源，世界艰难梭菌专家的指导和 粘膜免疫学，以及生物信息学领域的专家合作。我的职业发展计划 包括我的指导团队的结构化监督和指导，有针对性的课程工作，以获得 项目关键领域的技能(免疫学、生物信息学)，重点是加强教师队伍的讲习班 发展技能、出版基准和申请独立资助的计划，所有这些都将有所帮助 让我成为老年宿主感染领域的独立调查员。

PROJECT SUMMARY/ABSTRACT Significance: Clostridium difficile is the most common pathogen to cause healthcare-associated infections and has led to diarrheal diseases being the only cause of infectious diseases mortality in the United States to increase from 2000 to 2014. Not only are adults aged 65 or older more likely to be infected, they make up 90% of deaths from C. difficile infection (CDI). Research to look into mechanisms that increase the risk of deaths and severe outcome from CDI in the aged host is now more important than ever. Approach: Our preliminary studies show that aged mice have lower early innate immune responses and higher mortality from CDI, but these differences in mortality and immune responses with aging can be overcome by fecal microbiota transplant from young to aged mice. Using a novel aged mouse model of CDI we have developed, I will identify factors that mediate the protection in aged mice on the intestinal microbiome/metabolome side (Aim 1) and on the host response side (Aim 2). Aim 1 will analyze the microbiome and metabolome to identify protective bacteria and metabolites to test for protection against CDI in aged mice. Aim 2 will utilize RNA sequencing and flow cytometry to identify immune cells and pathways that mediate the microbiome effect on host response and test them by reversing the pathway during fecal transplant experiment. Combining findings from both aims will allow us to more completely characterize the pathogenesis and find targets for developing novel therapeutics. Career development: This proposal leverages the institutional commitment and training environment at University of Virginia, resources of the Warren/Guerrant Lab, mentorship from world experts on C. difficile and mucosal immunology, and expert collaborations in the field of bioinformatics. My career development plan includes structured oversight and guidance from my mentorship team, targeted coursework to acquire novel skills in key areas of the project (immunology, bioinformatics), focused workshops to enhance faculty development skills, publication benchmarks and plans to apply for independent funding, all of which will help establish me as an independent investigator in the field of infections in the aging host.