Host integration of commensal and pathogenic bacterial-derived signals

项目总结 肠道细菌感染仍然是全球最大的公共卫生挑战之一，并破译了 预防感染的机制将使新治疗方法的开发成为可能。肠道组织在 不断与各种有益和致病微生物直接接触，突出了协调的必要性 复杂的微生物信号，以维持对感染的保护。肠上皮细胞(IECS)位于 肠道病原体、有益共生菌和肠道免疫之间的直接接口 组件。然而，尽管不断接触不同的微生物，调控IECS如何 整合微生物衍生的信号以建立对病原体的保护性宿主反应还不是很清楚。 这项提议的目标是询问特定的共生细菌衍生的代谢物是如何被感觉到的。 通过IECS保护免受病原体感染。使用轮状柠檬酸杆菌，一种人类的小鼠模型 肠道致病性大肠埃希氏菌感染，我们的研究发现微生物区系衍生产品可以保护 防止肠道损伤和肠道细菌感染。我们对这个项目的表观遗传学分析导致了 直接调节IECS和主要宿主的新共生细菌代谢物的鉴定 防御病原细菌感染。利用一系列令人兴奋的转基因动物，致病 和共生细菌菌株，以及人类肠道有机化合物，提出了三个具体目标，将(I) 通过感知新发现的共生细菌破译宿主如何校准肠道屏障功能- 衍生代谢物，(Ii)研究肠道感染的代谢物依赖的调节，以及(Iii)询问如何 共生细菌对日粮成分的代谢启动表观基因组并增强宿主对 病原菌。定义整合共生和致病信号的途径将提供一种 测试操纵共生细菌衍生代谢物的治疗潜力以促进 抗菌免疫。

PROJECT SUMMARY Enteric bacterial infections remain one of the greatest public health challenges worldwide and deciphering the mechanisms that protect against infection will enable development of new treatments. Intestinal tissues are in constant direct contact with diverse beneficial and pathogenic microbes, highlighting the need for orchestrating complex microbial signals to sustain protection against infection. Intestinal epithelial cells (IECs) reside at the direct interface between intestinal pathogens, beneficial commensal bacteria, and intestinal immune components. However, despite continuous exposure to diverse microbes, the mechanisms regulating how IECs integrate microbial-derived signals to mount protective host responses to pathogens are not well understood. The goals of this proposal are to interrogate how specific commensal bacterial-derived metabolites are sensed by IECs to protect against pathogenic infection. Employing Citrobacter rodentium, a murine model of human enteropathogenic Escherichia coli infection, our studies have identified that microbiota-derived products protect against intestinal damage and enteric bacterial infection. Our epigenetic analyses for this project led to identification of new commensal bacterial-derived metabolites that can directly regulate IECs and prime host defense against pathogenic bacterial infection. Employing an exciting array of transgenic animals, pathogenic and commensal bacterial strains, and human intestinal organoids, three specific aims are proposed that will (i) decipher how the host calibrates intestinal barrier function by sensing newly-identified commensal bacterial- derived metabolites, (ii) investigate metabolite-dependent regulation of enteric infection, and (iii) interrogate how metabolism of dietary components by commensal bacteria prime the epigenome and enhance host response to pathogenic bacteria. Defining pathways that integrate commensal and pathogenic signals will provide a framework to test the therapeutic potential of manipulating commensal bacterial-derived metabolites to promote antibacterial immunity.