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

• 批准号: 10223165
• 负责人: William A Petri
• 金额: $ 78.12万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10223165
• 关键词: Adoptive Transfer; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Biometry; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinic; Clinical; Clostridium difficile; Colon; Communication; Data; Disease; Ensure; Environment; Failure; Foundations; Frequencies; Gnotobiotic; Human; Immune; Immune response; Immunity; Immunology; Immunotherapy; Infection; Infection prevention; Inflammation; Inflammatory Bowel Diseases; Interleukin-17; 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; Public Health; Publishing; RANTES; Recurrence; Relapse; Research; Research Personnel; Resolution; Risk; 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; success

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.

项目概要 简介：我们建议确定肠道 Th17 免疫反应的机制 导致严重和复发性艰难梭菌感染 (CDI) 并探索免疫系统 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：抗生素治疗 CDI 失败（即死亡或复发）是由于肠道 Th17 免疫 回复。 意义：艰难梭菌是美国五分之一的医院获得性感染的主要原因。 CDI 患者抗生素治疗失败，导致反复感染或死亡。 将探索免疫疗法是否可以改善 CDI 的治疗，特别是通过测试肠道的重要性 Th17 免疫反应对 CDI 严重程度和复发的影响 调查人员：弗吉尼亚大学的 William Petri 博士发现 17 型免疫会导致 CDI 期间疾病更加严重，这包括表明 IL-23 敲除小鼠的病情有所增加。 生存率、中性粒细胞流入减少和组织病理学减少 (Buonomo et al 2013)，Th17 极化细胞因子 IL-6 和 IL-23 与人类更严重的疾病（2 型）相关 免疫通过对抗 Th17 来提供保护 (Frisbee et al 2019)，并且 Th17 细胞的过继转移是 足以提高 CDI 死亡率（Saleh 等人，2019 年）。 Ann Hays 博士也参与了该研究。 UVA 复杂的艰难梭菌诊所以及 Jennie Ma 博士的生物统计专业知识。 创新：拟议的研究通过测试 Th17 细胞是否在严重 CDI 以及复发性 CDI 中发挥作用 CDI 将发生范式转变，因为这是一个过去专注于针对 该提案将测试是否诱导 Th17 免疫。 除了细菌和微生物群之外的反应也会引起疾病。 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) 具体目标 2：复发性 CDI - 测试 Th17 细胞和 Th17 招募趋化因子 CCL5 在 复发性CDI 具体目标 3：FMT – 确定 FMT 是否通过诱导 IL-33 来预防原发性和复发性 CDI 阻断 Th17 的作用。 环境：成功的关键是 Petri 实验室在粘膜免疫学方面的互补专业知识 肠道感染的研究，以及 Ann Hays 博士在 FMT 治疗复杂艰难梭菌感染方面的临床专业知识。