Innate immune defense against clostridium Difficile Infection

针对艰难梭菌感染的先天免疫防御

• 批准号: 9175987
• 负责人: Eric G. Pamer
• 金额: $ 40.69万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175987
• 关键词: Antibiotic Therapy; Antibiotics; Cells; Clinical; Clostridium; Clostridium difficile; Colitis; Colon; Complex; Diarrhea; Disease; Epithelial; Equilibrium; Frequencies; Gastrointestinal tract structure; Genes; Genetic Transcription; Germ-Free; Germination; Goals; Growth; Hospitalization; Human; IL18 gene; Immune; Immune system; Immunocompromised Host; Immunologics; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Ingestion; Interferons; Interleukin-12; Intervention; Intestines; Lymphocyte; Mediating; Mus; Outcome; Pathology; Patients; Predisposition; Production; Recovery; Regimen; Reproduction spores; Residual state; Resistance; Resistance to infection; Sampling; Secondary to; Severities; Severity of illness; Shotguns; Testing; Time; Toxin; abstracting; bile salts; cancer therapy; commensal microbes; cytokine; falls; insight; member; metabolome; metagenomic sequencing; microbiome; microbiota; monocyte; mortality; neutrophil; novel; older patient; prevent; reconstitution; research study; response; therapy development; transcriptome; transcriptome sequencing

Project Summary/Abstract Clostridium difficile is a leading cause of diarrhea in hospitalized patients and infection is acquired by ingestion of spores that germinate into toxin-producing vegetative forms that destroy colonic epithelial integrity. Intestinal inflammation induced by C. difficile requires spore germination within the GI tract, bacterial proliferation and toxin production leading to intestinal epithelial damage. C. difficile growth in the colon occurs when the composition of the commensal bacterial flora is damaged by antibiotic treatment. Specific members of the commensal flora inhibit C. difficile growth, in part by converting primary to secondary bile salts. Once C. difficile infection has damaged the colonic epithelial layer, the host’s immune system is activated and, while essential for host survival, also contributes to intestinal pathology. Inflammatory monocytes, neutrophils, innate lymphocytes (ILCs) and a range of inflammatory cytokines have been implicated in defense against C. difficile infection (CDI) and in inflammatory pathology. The goal of our studies is to identify and characterize microbiota and immune-mediated protective mechanisms and to test our discoveries on microbiologically and clinically diverse C. difficile strains. Our specific aims are: 1.) To assemble minimal-complexity commensal bacterial consortia derived from human fecal samples that provide high-level resistance against CDI. 2.) To characterize microbiota-mediated mechanisms that promote ILC1-mediated resistance against C. difficile and to test the hypothesis that the residual microbiota determines the balance of ILC1 versus ILC3 differentiation. 3.) To determine whether microbiota or ILC1 mediated defenses against CDI differ for distinct C. difficile strains. The proposed studies will provide novel insights into microbiota-mediated defenses against CDI and will also identify immune mechanisms that ameliorate adverse inflammatory responses during early CDI. These insights will facilitate the development of therapies to prevent and treat C. difficile infections.

项目总结/摘要 艰难梭菌是住院患者腹泻的主要原因，并且感染是通过 吞食孢子，孢子发芽成毒素产生的营养体，破坏结肠 上皮完整性C. difficile需要孢子在 胃肠道、细菌增殖和毒素产生导致肠上皮损伤。C. 当结肠细菌植物群的组成 被抗生素治疗破坏。植物植物群的特定成员抑制C.艰难的生长， 部分通过将伯胆汁盐转化为仲胆汁盐。一旦C.艰难的感染已经破坏了 结肠上皮层，宿主的免疫系统被激活，虽然对宿主生存至关重要， 也会导致肠道病变炎性单核细胞、中性粒细胞、先天性淋巴细胞 （ILC）和一系列炎性细胞因子参与了对C.艰难 感染（CDI）和炎症病理学。我们研究的目的是识别和表征 微生物群和免疫介导的保护机制，并测试我们的发现， 微生物和临床多样性C.艰难菌株我们的具体目标是：（1）组装 来自人类粪便样品的最小复杂性的肠道细菌聚生体， 对CDI的高水平抵抗。2.）的情况。为了表征微生物介导的机制， 促进ILC 1介导的对C.艰难的，并测试的假设，剩余的 微生物群决定了ILC 1与ILC 3分化的平衡。3.）第三章以确定是否 微生物群或ILC 1介导的对CDI的防御对于不同的C.艰难菌株拟议 研究将为微生物介导的CDI防御提供新的见解， 确定改善早期CDI期间不良炎症反应的免疫机制。 这些见解将促进预防和治疗C的疗法的发展。艰难感染。