Host integration of commensal and pathogenic bacterial-derived signals

共生菌和病原菌信号的宿主整合

• 批准号: 10161768
• 负责人: Theresa Alenghat
• 金额: $ 35.78万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-04 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161768
• 关键词: Animal Model; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Translocation; Binding; Butyrates; Bypass; Cause of Death; Cells; Child; Citrobacter; Citrobacter rodentium; Complex; Data; Development; Enteral; Enterobacteriaceae; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Escherichia coli; Escherichia coli Infections; Exposure to; Gene Expression; Genetic Transcription; Genome; Germ-Free; Goals; HDAC3 gene; Health; Histone Acetylation; Histone Deacetylase; Homeostasis; Host Defense; Human; Immune; Immune response; Immunity; In Vitro; Infection; Inositol Phosphates; Interleukin-18; Intestines; Mammalian Cell; Mediating; Mediator of activation protein; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; Nucleic Acid Regulatory Sequences; Organoids; Outcome Study; Pathogenicity; Pathway interactions; Pharmacology; Play; Population; Predisposition; Public Health; Regulation; Role; Signal Transduction; Testing; Tissues; Transgenic Animals; Transgenic Mice; Volatile Fatty Acids; Work; antimicrobial; beneficial microorganism; commensal bacteria; design; enteric infection; enteric pathogen; enteropathogenic Escherichia coli; epigenome; fighting; gain of function; gut microbiota; human model; immune activation; improved; in vivo; innovation; intestinal barrier; intestinal epithelium; microbial; microbiota; mortality; mouse model; novel; novel strategies; pathogen; pathogenic bacteria; pathogenic microbe; public health relevance; therapeutic evaluation; tool

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.

项目概要 肠道细菌感染仍然是全球最大的公共卫生挑战之一，并解读 防止感染的机制将使新疗法的开发成为可能。肠组织位于 与各种有益和病原微生物的持续直接接触，凸显了精心策划的必要性 复杂的微生物信号以维持免受感染的保护。肠上皮细胞（IEC）位于 肠道病原体、有益共生菌和肠道免疫之间的直接界面 成分。然而，尽管持续暴露于不同的微生物，但调节微生物的机制 IEC 整合微生物来源的信号来提高宿主对病原体的保护性反应，但效果不佳 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 信号并修改基因表达。该提案的目标是询问具体的共生性如何 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。采用啮齿类柠檬酸杆菌， 人类肠道病原性大肠杆菌感染的小鼠模型，我们的研究发现 HDAC3 可以保护 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 IEC 中的 HDAC3 功能，并且不同类型的共生细菌建立了独特的 IEC 中的组蛋白乙酰化特征。总的来说，这些数据表明 HDAC3 感知不同的代谢物 来自共生细菌的信号可在表观遗传上启动宿主对致病细菌的防御 感染。采用一系列令人兴奋的转基因动物、致病性和共生菌株，以及 人类肠道类器官，提出了三个具体目标，即（i）研究代谢物依赖性 肠道感染的调节，（ii）破译宿主如何通过感知不同的信号来校准肠道屏障功能 共生细菌衍生的代谢物，以及（iii）询问不同类型的共生细菌是否 启动表观基因组以增强宿主对病原菌的反应。定义整合途径 共生和致病信号将提供一个框架来测试操纵的治疗潜力 共生细菌衍生的代谢物可促进抗菌免疫力。