Role of Th17 in Severe and Recurrent C. difficile Infection

项目摘要 前言：我们建议确定肠道Th17免疫反应的机制 难治性梭状芽胞杆菌感染(CDI)与免疫学探讨 粪便微生物群移植(FMT)的保护机制。 假设：Th17细胞导致严重的CDI和复发。 前提：CDI抗生素治疗失败(即死亡或复发)是由于肠道Th17免疫 回应。 意义：艰难梭菌是美国医院获得性感染的主要原因。每五个人中就有一个 CDI患者未能接受抗生素治疗，结果是反复感染或死亡。这项建议 我将探索免疫疗法是否会改善CDI的治疗，特别是通过测试肠道的重要性 CDI严重程度和复发与Th17免疫反应的关系 研究人员：弗吉尼亚大学的威廉·佩里博士发现，17型免疫导致 CDI期间病情更为严重。这包括显示IL-23基因敲除的小鼠增加了 存活、减少中性粒细胞流入和减少组织病理(Buonomo等人，2013)，即Th17 极化细胞因子IL-6和IL-23与人类更严重的疾病有关，即2型 免疫通过对抗Th17来保护(Frisbee等人，2019年)，Th17细胞的过继转移是 足以提高CDI死亡率(Saleh等人，2019年)。安·海斯博士也加入了他的行列，她是 UVA复杂的艰难梭菌临床和珍妮·马博士的生物统计学专业知识。 创新：拟议中的研究通过测试Th17细胞是否在严重CDI和复发中发挥作用 CDI将转变范式，因为这是一个过去专注于目标的研究领域 细菌或微生物群用于治疗。相反，这项提议将测试Th17的诱导是否具有免疫力 反应除了细菌和微生物群外，都是引起疾病的原因。 方法： 具体目标1：严重CDI-确定Th17免疫反应导致严重CDI的机制 艰难梭菌感染(CDI) 特异性目标2：复发性CDI-检测Th17细胞和Th17-Recruiting趋化因子CCL5在 复发性CDI 具体目标3：FMT-确定FMT是否通过诱导IL-33保护原发和复发的CDI 阻断Th17的活动。 环境：成功的关键是佩里实验室在粘膜免疫学方面的互补专业知识 肠道感染，以及Ann Hays博士复杂艰难梭菌感染的FMT的临床专业知识。

Project Summary Introduction: We propose to Identify the mechanisms by which an intestinal Th17 immune response contributes to severe and recurrent Clostridioides difficile infection (CDI) and explore the immune mechanism by which fecal microbiota transplant (FMT) protects. Hypothesis: Th17 cells contribute to severe CDI and to recurrence. Premise: Failure of antibiotic treatment of CDI (i.e. death or recurrence) is due to a gut Th17 immune response. Significance: C. difficile is the leading cause of hospital-acquired infection in the United States. One in five patients with CDI fails antibiotic treatment and as a result suffers a recurrent infection or death. This proposal will explore if immunotherapy would improve treatment of CDI, specifically by testing the importance of gut Th17 immune responses in CDI severity and recurrence Investigators: Dr. William Petri at the University of Virginia has discovered that Type-17 immunity causes more severe disease during CDI. This has included showing that IL-23 knockout mice have increased survival, reduced neutrophil influx, and reduced tissue pathology (Buonomo et al 2013), that the Th17 polarizing cytokines IL-6 and IL-23 are associated with more severe disease in humans, that type 2 immunity protects by countering Th17 (Frisbee et al 2019), and that adoptive transfer of Th17 cells is sufficient to enhance CDI mortality (Saleh et al 2019). He is joined by Dr. Ann Hays who directs the complicated C. difficile clinic at UVA and the biostatistical expertise of Dr. Jennie Ma. Innovation: The proposed research by testing if Th17 cells have a role in severe CDI as well as recurrent CDI will be paradigm shifting, as this is a field of research that in the past has focused on targeting the bacterium or the microbiota for therapy. This proposal will instead test if the induction of a Th17 immune response in addition to the bacterium and microbiota are causing disease. Approach: Specific Aim 1: SEVERE CDI - Identify the mechanisms by which a Th17 immune response leads to severe C. difficile infection (CDI) Specific Aim 2: RECURRENT CDI - Test the role of Th17 cells and the Th17-recruiting chemokine CCL5 in recurrent CDI Specific Aim 3: FMT – Determine if FMT protects from primary and recurrent CDI by inducing IL-33 that blocks the action of Th17. Environment: Key to success are the complementary expertise of the Petri lab in the mucosal immunology of enteric infections, and the clinical expertise in FMT for complicated C. difficile infection of Dr. Ann Hays.