Molecular mechanisms of a multi-tissue innate immune response

项目概要/摘要 天然免疫作为获得性免疫的第一道防线和引物， 感染，其过度延长的激活促进慢性炎性疾病。而主 参与先天免疫的分子和信号通路已经确定，更多的研究是 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解决这个问题。黑腹果蝇是 先天免疫的发现，同样也被认为是理解分子生物学的一个极好的模型。 驱动更复杂的多组织先天免疫反应的机制。具体而言，我们建议 研究一种新的成年果蝇先天免疫反应模型，该模型涉及以下因素的组合： 免疫细胞（血细胞）、呼吸道上皮和解剖学共定位区域的储库 脂肪体的免疫组织在这个模型中，我们关注的是作为读数的Drosocin的表达， 促进细菌感染后的存活。我们发现血细胞，特别是它们通过NF κ B的信号传导- 相关的Imd途径，是诱导呼吸道上皮细胞中的屈索辛表达所必需的， 脂肪体的局部限制域。然而，尽管血细胞中的Imd信号传导是必需的，但它不是必需的。 足以触发屈索辛反应 我们假设免疫细胞充当细菌感染的哨兵，传递一种（迄今尚未确定的）信号。 呼吸道上皮和脂肪体，其作为响应上调屈索辛。屈索辛在 内源性表达水平，抗菌功能和促进细菌感染后的动物存活。 我们建议（1）识别在其他组织中触发屈索辛反应的血细胞信号，以及（2） 识别组织内传递屈索辛反应的信号通路。 这项工作是重要的，因为从这个果蝇模型的见解，预计将增加我们的 了解在各种疾病中驱动多组织先天免疫反应的分子机制， 跨门的生物，从而将“器官/组织间通讯”的概念扩展到先天性 免疫力该模型中确定的新的机械原理有望为脊椎动物研究提供信息， 激发抑制或增强多组织先天免疫反应的治疗方法， 针对各种医疗需求和条件定制。

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.