Epigenomic control of antimicrobial immunity in the intestine

肠道抗菌免疫的表观基因组控制

• 批准号: 9905513
• 负责人: Theresa Alenghat
• 金额: $ 35.79万
• 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: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905513
• 关键词: Adult; Anti-Bacterial Agents; Antibiotics; Bacterial Infections; Cells; Citrobacter; Citrobacter rodentium; Complex; Data; Development; Enterobacteriaceae; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Escherichia coli Infections; Exhibits; Gene Expression; Germ-Free; Goals; HDAC3 gene; Histone Acetylation; Homeostasis; Host Defense; Human; Immune; Immune response; Immunity; Immunotherapy; Impairment; Infection; Interleukin-18; Intestines; Knockout Mice; Lymphocyte; Lymphocyte Subset; Mammalian Cell; Mediating; Memory; Microbe; Modification; Molecular; Mus; Nuclear; Organoids; Outcome Study; Pathogenicity; Pathway interactions; Population; Predisposition; Production; Regulation; Reporter; Role; S100A8 gene; Severities; Signal Transduction; T-Cell Activation; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Translating; Work; active control; antimicrobial; antimicrobial peptide; bactericide; base; beneficial microorganism; combat; design; enteric infection; enteric pathogen; epigenetic regulation; epigenome; epigenomics; epithelial stem cell; host-microbe interactions; imprint; in utero; in vitro Assay; insight; intestinal crypt; intestinal epithelium; microbial; microbiota; mouse model; next generation; novel; novel therapeutics; overexpression; pathogenic bacteria; pathogenic microbe; progenitor; public health relevance; reconstitution; response; stem cells; tool

PROJECT SUMMARY Intestinal epithelial cells (IECs) that reside at the interface between the microbiota and diverse immune cell populations are critical for initiating and maintaining However, the mechanisms underlying how IECs tissue-intrinsic defenses needed to quickly combat infection. orchestrate the dynamic cross-talk between microbiota, epithelial cells, and lymphocytes remain poorly defined. Epigenetic-modifying enzymes represent a powerful, but poorly understood, interface by which mammalian cells can respond to microbial signals and regulate host response. We recently identified that IEC deletion of the epigenetic regulator HDAC3 in utero inhibited microbiota-dependent regulation of IECs and impaired activation of intestinal immune cells during infection. However, it remains unknown how HDAC3 in IECs actively governs intestinal immunity or sustains microbiota- sensitive defense against enteric infection. The goals of this proposal are to interrogate how differentiated and progenitor IECs actively control intestinal immune cell dynamics and microbiota-sensitive pathways needed for antibacterial immunity through epigenetic regulation. Based on new preliminary findings, we hypothesize that HDAC3 is an essential epithelial factor that (1) dynamically coordinates resident lymphocytes in the intestine and (2) primes short- and long-term IEC responsiveness to infection by integrating signals from the microbiota. Employing Citrobacter rodentium, a murine model of pathogenic human Escherichia coli infection, along with an exciting array of inducible transgenic mouse tools, germ-free mice, and human organoids, three specific aims are proposed to investigate these hypotheses. We will (i) interrogate how active regulation of IECs by HDAC3 directs tissue-resident lymphocyte dynamics and test how this epithelial-immune cell relationship is mechanistically controlled, (ii) directly examine how the microbiota promote epithelial antimicrobial secretion during infection, and (iii) employ reporter mice to define whether epigenetic regulation of stem cells mediates how the microbiota sustains long-term defense in the intestine. We will also translate our murine studies to human intestinal organoids to provide mechanistic insights on the role of HDAC3 and epigenetics in host-microbe interactions in human intestine. This work will uncover novel mechanisms for how IECs integrate microbial signals to instruct intestine-intrinsic immunity and guide design of next generation therapeutics that can epigenetically prime the intestine to effectively defend against enteric infections.

项目总结 肠道上皮细胞(IECS)，位于微生物区系和各种免疫细胞之间的界面上 种群对于启动和维护至关重要 然而，IECS背后的机制是 快速对抗感染所需的组织固有防御系统。 协调微生物区系之间的动态串扰， 上皮细胞和淋巴细胞的界限仍然很模糊。表观遗传修饰酶代表着一种强大的，但 哺乳动物细胞对微生物信号作出反应并调节宿主的界面，知之甚少 回应。我们最近发现，IEC在子宫内对表观遗传调节因子HDAC3的删除受到抑制 微生物依赖的IECS调节和肠道免疫细胞在感染过程中的激活受损。 然而，目前尚不清楚IECS中的HDAC3是如何积极调控肠道免疫或维持微生物区系的。 对肠道感染的敏感防御。这项提议的目标是询问如何区分和 祖细胞IECS主动控制肠道免疫细胞动力学和微生物敏感途径 通过表观遗传调节的抗菌免疫。根据新的初步发现，我们假设 HDAC3是一种基本的上皮因子，它(1)动态协调肠道内的常驻淋巴细胞和 (2)通过整合来自微生物区系的信号来启动IEC对感染的短期和长期反应。 利用轮状柠檬酸杆菌，一种致病性人类大肠杆菌感染的小鼠模型，以及一个 令人兴奋的一系列可诱导的转基因小鼠工具、无菌小鼠和人类器官，三个特定的目标 来研究这些假说。我们将(I)询问HDAC3对IECS的积极监管 指导组织驻留的淋巴细胞动力学，并测试这种上皮细胞和免疫细胞的关系 机械控制，(Ii)直接检查微生物区系如何促进上皮抗菌物质的分泌 以及(Iii)使用报告鼠来确定干细胞的表观遗传调控是否介导了 微生物区系如何维持肠道的长期防御。我们还将把我们的小鼠研究转化为 人类肠道有机体提供对HDAC3和表观遗传学在宿主微生物中的作用的机械性见解 人体肠道内的相互作用。这项工作将揭示IECS如何整合微生物的新机制 指示肠道固有免疫的信号，并指导下一代疗法的设计 表观遗传学为肠道做好准备，以有效防御肠道感染。