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，调节如何 IECS整合微生物衍生的信号以保护宿主对病原体的反应不好 明白了。表观遗传变化代表了一个强大的界面，使细胞能够对环境做出反应 信号和修改基因表达。这项提议的目的是询问如何具体地共生 调节表观遗传修饰酶组蛋白脱乙酰酶3(HDAC3)的细菌衍生代谢物 影响肠道对感染和细菌移位的保护。使用轮状柠檬酸杆菌， 人致病性大肠埃希氏菌感染小鼠模型的研究证实HDAC3对 抗肠道细菌感染。新的初步数据表明，共生细菌衍生的代谢物可以 直接调节IECS中HDAC3功能，不同类型的共生菌建立独特的 IECS中组蛋白乙酰化信号。总而言之，这些数据表明HDAC3感知不同的代谢物 来自共生细菌的信号，以表观遗传方式启动宿主对病原菌的防御 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，提出了三个特定的目标，将(I)研究代谢物依赖 肠道感染的调节，(Ii)破译宿主如何通过感知不同的 以及(Iii)询问不同类型的共生细菌 启动表观基因组以增强宿主对病原菌的反应。定义集成的路径 共生和致病信号将提供一个框架，以测试操纵的治疗潜力 共生细菌衍生的代谢物，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. Epigenetic changes represent a powerful interface that enable cells to respond to environmental signals and modify gene expression. The goals of this proposal are to interrogate how specific commensal bacterial-derived metabolites that regulate the epigenetic-modifying enzyme histone deacetylase 3 (HDAC3) influence intestinal protection against infection and bacterial translocation. Employing Citrobacter rodentium, a murine model of human enteropathogenic Escherichia coli infection, our studies identified that HDAC3 protects against enteric bacterial infection. New preliminary data suggest commensal bacterial-derived metabolites can directly modulate HDAC3 function in IECs and that distinct types of commensal bacteria establish unique histone acetylation signatures in IECs. Collectively, these data suggest that HDAC3 senses distinct metabolite signals derived from commensal bacteria to epigenetically 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) investigate metabolite-dependent regulation of enteric infection, (ii) decipher how the host calibrates intestinal barrier function by sensing distinct commensal bacterial-derived metabolites, and (iii) interrogate whether distinct types of commensal bacteria prime the epigenome to 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.