Enterotoxigenic Bacteroides fragilis in modulation of host immunity

产肠毒素脆弱拟杆菌对宿主免疫的调节作用

• 批准号: 10318195
• 负责人: Juliane Bubeck Wardenburg
• 金额: $ 23.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318195
• 关键词: Adult; Affect; Anaerobic Bacteria; Anatomy; Antigen Presentation; Antigens; Architecture; Bacterial Antigens; Bacterial Toxins; Bacteroides; Bacteroides fragilis; Biological Models; Birth; Bypass; Cells; Chronic; Clinical; Clostridium difficile; Colitis; Colon; Colon Carcinoma; Colonic Diseases; Complex; Development; Diarrhea; Disease; Disease susceptibility; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Event; Exposure to; Fluorescence Microscopy; Genetic; Genetic Determinism; Goals; Goblet Cells; Health; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intervention; Intestinal Diseases; Intestines; Knowledge; Lamina Propria; Life; Maintenance; Malignant Neoplasms; Mammals; Mediating; Metalloproteases; Microbe; Modeling; Modification; Mus; Myeloid Cells; Neonatal; Organism; Outcome; Pathogenesis; Pathology; Population; Positioning Attribute; Predisposition; Probiotics; Process; Public Health; Regulatory T-Lymphocyte; Risk; Role; Sampling; Shapes; System; T cell response; T-Cell Development; T-Lymphocyte; Time; Toxin; Variant; Vertical Disease Transmission; Weaning; antigen-specific T cells; base; cell injury; colon microbiome; colon microbiota; critical developmental period; dysbiosis; germ free condition; gut microbiome; gut microbiota; human microbiota; immunoregulation; insight; intestinal epithelium; member; microbial; microbiome; microbiota; microorganism; microorganism antigen; mouse model; mutant; neonatal mice; neonate; novel; nutrition; pathobiont; postnatal; response; symbiont; trait; uptake

PROJECT SUMMARY Humans and other mammals are colonized by a plethora of microorganisms at the time of birth. The constellation of microorganisms that inhabit the gut is key in the development of the host immune system. It is increasingly clear that early events in development of the colonic microbiota influence host immunity, nutrition, and susceptibility to disease, yet specific mechanistic insights on these processes remain limited. Inflammatory bowel disease (IBD) and colonic malignancy are heterogeneous diseases that emerge as a result of a complex interplay of host genetic and environmental factors, including the composition and function of the gut microbiota. Bacteroides fragilis represents up to 2.5% of the human gut microbiota and is often found in neonates within the first month of life. A subset of Bacteroides fragilis strains termed enterotoxigenic B. fragilis (ETBF) secretes B. fragilis toxin (BFT), a metalloprotease that causes inflammatory damage of the intestinal epithelium. ETBF has been found as strongly associated to the pathogenesis of colonic disease, yet also colonizes up to 20% of asymptomatic humans, suggesting that these individuals may carry a potential long- term health risk as part of their stable gut microbiome. The primary goal of this proposal is to examine the effects of early life acquisition of ETBF on the immune system, based on the hypothesis that ETBF can dramatically alter T cell specific responses. These studies will benefit from the use of a novel model of B. fragilis vertical transmission in which the temporal and genetic determinants of initial niche colonization by B. fragilis can be evaluated in neonatal mice. Through a comprehensive genetically- and temporally-dissected analysis of antigen-specific T cell responses to ETBF during neonatal colonization, this study aims at defining fundamental principles that underlie ETBF-mediated disease through analysis of luminal antigen sampling and BFT-dependent modulation of immune response. We will also explore the possibility that ETBF allows for other members of the microbiota to access the lamina propria niche, further disrupting development of the immune system. Overall, our proposed studies will provide mechanistic insights of early life effects of BFT on the immune system, emphasizing the impact on tolerance to Bacteroides-specific and other colonic luminal antigens.

项目摘要 人类和其他哺乳动物在出生时被大量的微生物殖民。这 居住在肠道的微生物的星座是宿主免疫系统发展的关键。这是 越来越清楚的是，结肠微生物群发育中的早期事件会影响宿主免疫，营养， 以及对疾病的敏感性，但对这些过程的具体机理见解仍然有限。炎症 肠道疾病（IBD）和结肠恶性肿瘤是由于复合物而出现的异质性疾病 宿主遗传和环境因素的相互作用，包括肠道的组成和功能 微生物群。细菌脆弱的fragilis代表人类肠道菌群的2.5％，通常在 在生命的第一个月内新生儿。一部分被称为肠毒素B. fragilis的菌属菌株的一部分 （ETBF）分泌B. fragilis毒素（BFT），这是一种金属蛋白酶，会造成肠道炎症损伤 上皮。已经发现ETBF与结肠疾病的发病机理密切相关，但也 殖民多达20％的无症状人类，这表明这些人可能具有潜在的长期 术语健康风险是其稳定肠道微生物组的一部分。该提议的主要目标是检查 基于ETBF可以的假设，ETBF早期恢复生命对免疫系统的影响 急剧改变T细胞特异性响应。这些研究将受益于使用新型模型。 脆弱的垂直传播，其中的时间和遗传决定因素。 可以在新生小鼠中评估脆弱性。通过全面的遗传和时间拖延 在新生儿定植期间对抗原特异性T细胞对ETBF的反应，本研究旨在定义 通过分析腔抗原采样和 免疫反应的BFT依赖性调节。我们还将探讨ETBF允许其他其他的可能性 微生物群的成员进入固有层，进一步破坏了免疫的发展 系统。总体而言，我们提出的研究将提供BFT早期生活影响的机械见解 免疫系统，强调对细菌特异性和其他结肠腔的耐受性的影响 抗原。