Epigenomic control of antimicrobial immunity in the intestine

项目摘要 肠上皮细胞（IEC）位于微生物群和多种免疫细胞之间的界面 人口对于启动和维持 然而，独立选举委员会 快速对抗感染所需的组织内在防御。 协调微生物群之间的动态串扰， 上皮细胞和淋巴细胞仍然不清楚。表观遗传修饰酶代表了一种强大的， 哺乳动物细胞对微生物信号作出反应并调节宿主的界面， 反应我们最近发现，IEC在子宫内删除表观遗传调节因子HDAC 3， 在感染过程中，微生物群依赖性调节IEC和受损的肠道免疫细胞活化。 然而，目前尚不清楚IEC中的HDAC 3如何积极控制肠道免疫或维持微生物群。 对肠道感染的敏感防御。该提案的目标是询问如何区分和 前体IEC积极控制肠道免疫细胞动力学和微生物群敏感的途径， 通过表观遗传调节获得抗菌免疫力。基于新的初步发现，我们假设， HDAC 3是一种必需的上皮因子，其（1）动态协调肠中的驻留淋巴细胞， (2)通过整合来自微生物群的信号，启动短期和长期IEC对感染的反应。 使用啮齿柠檬酸杆菌，一种致病性人大肠杆菌感染的小鼠模型，沿着 一系列令人兴奋的诱导型转基因小鼠工具，无菌小鼠和人类类器官，三个具体目标 提出了调查这些假设。我们将（i）询问HDAC 3如何主动调节IEC 指导组织驻留淋巴细胞动力学，并测试这种上皮细胞-免疫细胞关系是如何 （ii）直接检查微生物群如何促进上皮抗微生物分泌 在感染期间，和（iii）使用报告小鼠来确定干细胞的表观遗传调节是否介导 微生物群如何维持肠道的长期防御。我们还将把我们的鼠类研究转化为 人类肠道类器官，以提供关于HDAC 3和表观遗传学在宿主微生物中的作用的机制见解 在人体肠道中的相互作用。这项工作将揭示IEC如何整合微生物的新机制 信号，以指导免疫系统的内在免疫和指导下一代治疗的设计， 在表观遗传学上，肠道可以有效地抵御肠道感染。

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.