Host integration of commensal and pathogenic bacterial-derived signals

项目摘要 肠道细菌感染仍然是全球最大的公共卫生挑战之一， 防止感染的机制将使新的治疗方法得以发展。肠道组织在 与各种有益和致病微生物的持续直接接触，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（IEC）位于 肠道病原体、有益肠道细菌和肠道免疫之间的直接界面 件.然而，尽管持续暴露于不同的微生物，调节IEC如何 整合微生物来源信号以建立对病原体的保护性宿主应答还没有很好地理解。 这项建议的目标是询问如何具体的肠道细菌衍生的代谢产物被感知 以防止病原体感染。使用啮齿柠檬酸杆菌，一种人类的小鼠模型， 肠致病性大肠杆菌感染，我们的研究已经确定，微生物衍生的产品保护 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分析导致了 直接调节IEC和原宿主新的肠道细菌衍生代谢产物的鉴定 防御病原性细菌感染。利用一系列令人兴奋的转基因动物， 和肠道细菌菌株以及人类肠道类器官，提出了三个具体目标，将（i） 破译宿主如何通过感知新发现的肠道细菌来校准肠道屏障功能， 衍生代谢物，（ii）研究肠道感染的代谢依赖性调节，以及（iii）询问如何 肠道细菌对食物成分的代谢启动表观基因组，增强宿主对 致病菌定义整合神经和致病信号的途径将提供一个 框架来测试操纵肠道细菌衍生的代谢物以促进 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.