Innate immune defense against clostridium Difficile Infection

项目摘要/摘要 艰难梭菌是住院患者腹泻的主要原因，感染是通过 摄取萌发成产生毒素的营养形态的孢子，从而破坏结肠 上皮完整性。艰难梭菌引起的肠道炎症需要孢子萌发 肠道细菌的增殖和毒素的产生导致肠道上皮损伤。C。 当共生菌群的组成是 因抗生素治疗而受损。共生菌的特定成员抑制艰难梭菌的生长， 部分是通过将初级胆盐转化为次级胆盐。一旦艰难梭菌感染破坏了 结肠上皮层，宿主的免疫系统被激活，虽然对宿主的生存至关重要， 对肠道病理也有贡献。炎性单核细胞、中性粒细胞、固有淋巴细胞 ILCs和一系列炎性细胞因子与艰难梭菌的防御有关 感染(CDI)和炎性病理。我们研究的目标是识别和描述 微生物区系和免疫介导的保护机制，并测试我们在 微生物学和临床上多样化的艰难梭菌菌株。我们的具体目标是：1.)装配，装配 从人类粪便样本中衍生的最小复杂性共生细菌联合体 对CDI的高水平阻力。2.)为了表征微生物区系介导的机制， 促进ILC1介导的对艰难梭菌的耐药性，并检验残留物 微生物区系决定了ILC1和ILC3分化的平衡。3.)以确定是否 对于不同的艰难梭菌菌株，微生物区系或ILC1介导的对CDI的防御不同。建议数 研究将为微生物群介导的CDI防御提供新的见解，并将 确定在CDI早期减轻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。

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.