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: 10055905
• 负责人: Eric G. Pamer
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF CHICAGO
• 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/10055905
• 关键词: Innate; immune; defense; against; clostridium

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.

项目概要/摘要 艰难梭菌是住院患者腹泻的主要原因，感染是通过以下途径获得的： 摄入孢子，孢子会发芽成产生毒素的植物形式，破坏结肠 艰难梭菌诱导的肠道炎症需要孢子在其内萌发。 胃肠道、细菌增殖和毒素产生导致肠上皮损伤 C. 当共生菌群的组成为 共生菌群的特定成员受到抗生素治疗的破坏，抑制艰难梭菌的生长， 部分是通过将初级胆汁盐转化为次级胆汁盐。 结肠上皮层，宿主的免疫系统被激活，并且对于宿主的生存至关重要， 也有助于肠道病理学。 (ILC) 和一系列炎症细胞因子与艰难梭菌的防御有关 感染（CDI）和炎症病理学我们研究的目标是识别和表征。 微生物群和免疫介导的保护机制，并测试我们的发现 我们的具体目标是：1.) 组装微生物学和临床上多样化的艰难梭菌菌株。 源自人类粪便样本的最小复杂性共生细菌群落，提供 2.) 表征微生物介导的机制 促进 ILC1 介导的对艰难梭菌的耐药性，并检验残留的假设 微生物群决定 ILC1 与 ILC3 分化的平衡 3.) 确定是否。 对于不同的艰难梭菌菌株，微生物群或 ILC1 介导的针对 CDI 的防御有所不同。 研究将为微生物介导的 CDI 防御提供新的见解，并且还将 确定改善早期 CDI 期间不良炎症反应的免疫机制。 这些见解将有助于开发预防和治疗艰难梭菌感染的疗法。