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: 10443698
• 负责人: William A Petri
• 金额: $ 78.41万
• 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/10443698
• 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.

项目摘要 引言：我们建议确定肠道Th 17免疫应答的机制， 导致严重和复发性艰难梭菌感染（CDI），并探索免疫 粪便微生物群移植（FMT）的保护机制。 假设：Th 17细胞导致严重的CDI和复发。 结论：CDI抗生素治疗失败（即死亡或复发）是由于肠道Th 17免疫 反应 显著性：C.艰难梭菌是美国医院获得性感染的主要原因。五分之一 患有CDI的患者抗生素治疗失败，结果遭受复发性感染或死亡。这项建议 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严重程度和复发中的Th 17免疫应答 调查人员：弗吉尼亚大学的威廉·佩特里博士发现，17型免疫导致 在CDI期间更严重的疾病。这包括显示IL-23敲除小鼠增加了 存活率、减少的中性粒细胞流入和减少的组织病理学（Buonomo et al 2013），Th 17 极化细胞因子IL-6和IL-23与人类更严重的疾病相关， 免疫通过对抗Th 17来保护（Frisbee et al 2019），Th 17细胞的过继转移是 足以提高CDI死亡率（Saleh et al 2019）。安·海斯博士也加入了他的行列， 复杂C弗吉尼亚大学的difficile诊所和Dr. J. Ma的生物统计专业知识。 创新：通过测试Th 17细胞是否在严重CDI以及复发性CDI中发挥作用， CDI将是范式转变，因为这是一个过去专注于针对 细菌或微生物群用于治疗。该提议将改为测试Th 17免疫的诱导是否 除了细菌和微生物群的反应是导致疾病。 方法： 具体目标1：严重CDI -确定Th 17免疫应答导致严重CDI的机制 C.艰难梭菌感染 具体目标2：复发CDI -测试Th 17细胞和Th 17募集趋化因子CCL 5在 复发性CDI 具体目标3：FMT -确定FMT是否通过诱导IL-33， 阻断Th 17的作用。 环境：成功的关键是培养式实验室在粘膜免疫学方面的互补专业知识 以及FMT治疗复杂C.安·海斯医生的艰难感染