Role of Th17 in Severe and Recurrent C. difficile Infection

Th17 在严重和复发性艰难梭菌感染中的作用

基本信息

批准号：
10653065
负责人：
William A Petri
金额：
$ 78.34万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653065
关键词：
Adoptive Transfer Antibiotic Therapy Antibiotics Antimicrobial Resistance Bacteria Biometry CCR5 gene CD4 Positive T Lymphocytes Cells Cessation of life Clinic Clinical Clostridium difficile Colon Communication Data Disease Ensure Environment Failure Foundations Frequencies Gnotobiotic Human IL17 gene Immune Immune response Immunity Immunology Immunotherapy Infection Infection prevention Inflammation Inflammatory Bowel Diseases Interleukin-6 Intestines Knock-out Knockout Mice Leukocyte L1 Antigen Complex Mediating Microbe Mucous Membrane Mus Nature Neutralization Tests North America Nosocomial Infections Oligonucleotides Pathology Patients Population Predisposition Proliferating Public Health Publishing RANTES Recurrence Relapse Research Research Personnel Resolution Role Severities Sodium Dextran Sulfate T-Cell Depletion Testing Tissues United States Universities Virginia Work chemokine commensal bacteria cytokine dextran sulfate sodium induced colitis enteric infection fecal transplantation gut microbiota improved innovation interleukin-23 mesenteric lymph node microbiota mortality mouse model neutralizing monoclonal antibodies neutrophil patient response peripheral blood prevent programs receptor recruit recurrent infection relapse risk response risk prediction success

项目摘要

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.

项目摘要简介：我们建议确定肠道Th17免疫反应的机制有助于严重和经常性的梭菌艰难梭菌感染（CDI）并探索免疫粪便菌群移植（FMT）保护的机制。假设：Th17细胞有助于严重的CDI和复发。前提：CDI的抗生素治疗失败（即死亡或复发）是由于肠道Th17免疫回复。意义：艰难梭菌是美国医院获得感染的主要原因。五分之一 CDI患者失败了抗生素治疗，因此复发感染或死亡。这个建议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严重性和复发中的TH17免疫调查调查人员：弗吉尼亚大学的威廉·佩特里（William Petri）博士发现，17型免疫学原因 CDI期间更严重的疾病。这包括表明IL-23淘汰小鼠增加了生存，中性粒细胞影响减少和减少组织病理学（Buonomo等，2013），Th17 偏振细胞因子IL-6和IL-23与人类中更严重的疾病有关，该2型免疫力通过反击Th17（Frisbee等，2019）来保护，而Th17细胞的适应性转移是足以提高CDI死亡率（Saleh等人，2019年）。安·海斯博士（Ann Hays）加入了他的行列 UVA的复杂艰难梭菌诊所和MA Jennie Ma博士的生物统计学专业知识。创新：通过测试Th17细胞是否在严重的CDI以及经常性中作用的拟议研究 CDI将是范式的转移，因为这是一个研究领域，过去一直集中在目标上细菌或菌群进行治疗。该提案将测试是否诱导Th17免疫除了细菌和微生物群外，还引起疾病。方法：特定目标1：严重的CDI-确定Th17免疫响应导致严重的机制艰难梭菌感染（CDI）特定目标2：复发CDI-测试Th17细胞和Th17征收趋化因子CCL5在中的作用经常性CDI 特定目标3：FMT - 确定FMT是否通过诱导的IL-33保护FMT是否可以免受原发性和复发性CDI的侵害。阻止了TH17的动作。环境：成功的关键是粘膜免疫学中培养皿实验室的完整专业知识肠道感染以及Ann Hays博士艰难梭菌感染的FMT的临床专业知识。