Molecular mechanisms of a multi-tissue innate immune response

多组织先天免疫反应的分子机制

• 批准号: 10178043
• 负责人: DANA LEANNE JONES
• 金额: $ 34.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178043
• 关键词: Address; Adult; Air Sacs; Anatomy; Animals; Anti-Bacterial Agents; Bacterial Infections; Candidate Disease Gene; Cells; Chest; Communicable Diseases; Communication; Complex; Disease; Drosophila genus; Drosophila melanogaster; Event; Fat Body; Genes; Genetic; Genetic Epistasis; Goals; Head; Health; Heart; Hemocytes; Human; Immune; Immune response; Immune signaling; Infection; Inflammatory; Innate Immune Response; Invertebrates; Maintenance; Mediating; Medical; Mission; Modeling; Molecular; Natural Immunity; Organ; Organism; Pathway interactions; Play; Public Health; RNA Interference; RNA interference screen; Research; Role; Sentinel; Signal Pathway; Signal Transduction; Structure of respiratory epithelium; System; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; adaptive immunity; antimicrobial; antimicrobial peptide; base; chronic inflammatory disease; in vivo; innate immune mechanisms; insight; overexpression; response; screening

PROJECT SUMMARY/ABSTRACT Innate immunity plays important roles as first line defense and primer for adaptive immunity to protect against infection, and its excessive prolonged activation promotes chronic inflammatory diseases. While the main molecular players and signaling pathways involved in innate immunity have been identified, more research is needed to understand how signaling among multiple tissues triggers innate immune responses at the organismal level. Since studying multi-tissue innate immune responses remains challenging in vertebrate systems, we address this question in a simple invertebrate model. Drosophila melanogaster has been key in the discovery of innate immunity, and it is likewise expected to be an excellent model to understand molecular mechanisms that drive more complex, multi-tissue innate immune responses. Specifically, we propose to investigate a new model of an innate immune response in adult Drosophila, which involves the combination of a reservoir of immune cells (hemocytes), respiratory epithelium, and domains of the anatomically colocalizing immune tissue of the fat body. In this model, we focus on the expression of Drosocin as a readout, which promotes survival after bacterial infection. We find that hemocytes, and specifically their signaling by the NFkB- related Imd pathway, are required for the induction of Drosocin expression in the respiratory epithelium and locally restricted domains of the fat body. However, while Imd signaling in hemocytes is required, it is not sufficient to trigger the Drosocin response. We hypothesize that immune cells act as sentinels of bacterial infection that relay a (so far unidentified) signal to the respiratory epithelium and fat body, which in response upregulate Drosocin. Drosocin has, at endogenous expression levels, anti-bacterial function and promotes animal survival after bacterial infection. We propose to (1) identify hemocyte signal/s that trigger the Drosocin response in other tissues, and (2) identify the signaling pathways within tissues that relay the Drosocin response. This work is significant because insights from this Drosophila model are expected to increase our understanding of the molecular mechanisms that drive multi-tissue innate immune responses in a variety of organisms across phyla, thereby extending the concept of `inter-organ/-tissue communication' to innate immunity. New mechanistic principles identified in this model are expected to inform vertebrate research and inspire therapeutic approaches that curb or enhance multi-tissue innate immune responses, which could be tailored toward a variety of medical needs and conditions.

项目概要/摘要 先天免疫作为一线防御和适应性免疫的引物发挥着重要作用，以防止 感染及其过度长时间激活会促进慢性炎症性疾病。虽然主要 涉及先天免疫的分子参与者和信号通路已被确定，更多的研究正在进行中 需要了解多个组织之间的信号传导如何触发先天免疫反应 有机体水平。由于研究脊椎动物的多组织先天免疫反应仍然具有挑战性 系统，我们在一个简单的无脊椎动物模型中解决这个问题。果蝇是关键 先天免疫的发现，同样有望成为理解分子免疫的绝佳模型 驱动更复杂的多组织先天免疫反应的机制。具体来说，我们建议 研究成年果蝇先天免疫反应的新模型，该模型涉及以下组合： 免疫细胞（血细胞）、呼吸道上皮和解剖学共定位域的储存库 脂肪体的免疫组织。在此模型中，我们重点关注 Drosocin 的表达作为读数，其中 促进细菌感染后的存活。我们发现血细胞，特别是它们通过 NFkB 发出的信号 相关的 Imd 途径，是诱导呼吸道上皮中 Drosocin 表达所必需的，并且 脂肪体的局部限制区域。然而，虽然血细胞中的 Imd 信号传导是必需的，但它不是 足以触发 Drosocin 反应。 我们假设免疫细胞充当细菌感染的哨兵，传递（迄今为止尚未识别的）信号 呼吸道上皮和脂肪体，从而上调 Drosocin。 Drosocin 具有，在 内源性表达水平、抗菌功能并促进细菌感染后动物的存活。 我们建议 (1) 识别在其他组织中触发 Drosocin 反应的血细胞信号，以及 (2) 识别组织内传递 Drosocin 反应的信号通路。 这项工作意义重大，因为来自该果蝇模型的见解预计将增加我们的研究成果。 了解驱动多种组织先天免疫反应的分子机制 跨门的生物体，从而将“器官间/组织间通讯”的概念扩展到先天 免疫。该模型中确定的新机制原理有望为脊椎动物研究和 激发抑制或增强多组织先天免疫反应的治疗方法，这可能是 针对各种医疗需求和条件量身定制。