Enterotoxigenic Bacteroides fragilis in modulation of host immunity

项目摘要 人类和其他哺乳动物在出生时就被大量的微生物所殖民。的 栖息在肠道中的微生物群是宿主免疫系统发育的关键。是 越来越清楚的是，结肠微生物群发育的早期事件影响宿主免疫、营养 和对疾病的易感性，但对这些过程的具体机制的见解仍然有限。炎性 肠道疾病（IBD）和结肠恶性肿瘤是异质性疾病， 宿主遗传和环境因素的相互作用，包括肠道的组成和功能 微生物群脆弱拟杆菌占人类肠道微生物群的2.5%，通常存在于 新生儿在生命的第一个月内。脆弱拟杆菌菌株的一个子集，称为肠致病性B。脆弱拟 （ETBF）分泌B。脆壁毒素（BFT），一种金属蛋白酶，可引起肠道炎症性损伤 上皮已经发现ETBF与结肠疾病的发病机制密切相关，然而， 在20%的无症状人群中定植，这表明这些人可能携带潜在的长期- 长期健康风险作为其稳定肠道微生物组的一部分。本提案的主要目的是审查 早期获得ETBF对免疫系统的影响，基于ETBF可以 显著改变T细胞特异性反应。这些研究将受益于一种新的B模型的使用。 fragilis垂直传播，其中的时间和遗传决定因素的初始生态位定植的B。 fragilis可以在新生小鼠中评估。通过全面的基因和时间解剖 分析新生儿定植期间对ETBF的抗原特异性T细胞应答，本研究旨在确定 通过管腔抗原采样分析ETBF介导疾病的基本原理， BFT依赖性免疫应答调节。我们还将探讨ETBF允许其他 微生物群的成员进入固有层生态位，进一步破坏免疫系统的发育。 系统总的来说，我们提出的研究将提供BFT对早期生活影响的机制见解。 免疫系统，强调对类杆菌特异性和其他结肠腔的耐受性的影响 抗原

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.