Control of intestinal innate immunity by the commensal microbiota in a model host

摘要/项目摘要 微生物与肠道上皮细胞相互作用，调节对感染、营养不良、 以及肥胖和糖尿病等慢性代谢性疾病的易感性。然而，主机信令 微生物用来促进健康和疾病的途径知之甚少。强大的基因 模型节肢动物黑腹果蝇提供的工具使许多发现成为可能，这些发现形成了 是我们对先天免疫的现代理解的基础。在这里，我们打算利用果蝇 定义检测肠道微生物的宿主信号通路并协调 肠上皮的先天免疫反应。 果蝇肠道干细胞、肠细胞和肠内分泌细胞(EECS)的功能类似于 哺乳动物的肠道。肠上皮细胞占肠道上皮细胞的5%-10%，分泌 肠内分泌肽(EEPS)，调节宿主代谢功能，如胰岛素信号、饱腹感和 肠道收缩。我们已经确定了EECs的一个子集，它对微生物有独特的反应 通过肿瘤坏死因子样免疫缺陷激活天然免疫信号的发酵产物醋酸酯 (IMD)途径。在这些EEC中，IMD信号增加了编码EEPS的基因的转录。这些 EEPS反过来协调肠道中不同类型的细胞对微生物的反应。在这里我们 研究微生物激活肠道先天免疫反应的机制和最终的 这一调控途径对感染易感性的影响。 在这个方案中，我们将研究染色质重塑在醋酸盐介导的IMD信号转导中的作用 肽聚糖在肠道IMD信号转导中的作用，EEPS作为细胞因子的作用，最后细胞- EEPS在调节肠道感染易感性中的特殊作用。这样做的首要目标是 研究旨在揭示肠道对微生物的先天免疫反应的新范例，目标是 改善营养不良、慢性代谢性疾病和易感性的营养利用的通知疗法 肠道感染。

Abstract/Project Summary Microbes interact with the intestinal epithelium in ways that modulate susceptibility to infection, malnutrition, and predisposition to chronic metabolic diseases such as obesity and diabetes. However, the host signaling pathways utilized by microbes to promote health and disease are poorly understood. The powerful genetic tools provided by the model arthropod Drosophila melanogaster have enabled many discoveries that form the basis of our modern understanding of innate immunity. Here we propose to exploit the Drosophila melanogaster model to define the host signaling pathways that detect intestinal microbes and orchestrate the innate immune response of the intestinal epithelium. Drosophila intestinal stem cells, enterocytes and enteroendocrine cells (EECs) carry out functions similar to those of the mammalian intestine. EECs, which constitute 5-10% of cells in the intestinal epithelium, secrete enteroendocrine peptides (EEPs) that modulate host metabolic functions such as insulin signaling, satiety, and intestinal contractions. We have identified a subset of EECs that responds uniquely to the microbial fermentation product acetate by activating innate immune signaling through the TNF-like Immunodeficiency (IMD) pathway. In these EECs, IMD signaling increases transcription of the genes encoding EEPs. These EEPs, in turn, coordinate the response of the diverse cell types in the intestine to microbes. Here we investigate the mechanism by which microbes activate the intestinal innate immune response and the ultimate impact of this regulatory pathway on susceptibility to infection. In this proposal, we will investigate the role of chromatin remodeling in acetate-mediated IMD signaling, the contribution of peptidoglycan to intestinal IMD signaling, the role of EEPs as cytokines, and finally the cell- specific roles of EEPs in modulating susceptibility to intestinal infection. The overarching objective of this research is to uncover novel paradigms of the intestinal innate immune response to microbes with the goal of informing therapies that modify nutrient utilization in malnutrition, chronic metabolic diseases and susceptibility to intestinal infection.