SNARE-mediated protein trafficking in macrophages

巨噬细胞是白色血细胞，其通过摄取或吞噬微生物引发炎症反应并通过释放可溶性信使（细胞因子）以募集其他免疫细胞来提供对抗感染的前线防御。这些防御功能需要在巨噬细胞内广泛运输蛋白质。蛋白质运输部分由称为SNARE的膜融合蛋白家族协调。通过定义相关的SNARE，我们最近发现了一个备受赞誉的新途径，允许有效的，组合的细胞因子分泌和吞噬巨噬细胞。我们在这里提出的研究现在将通过比较吞噬过程来扩展这一发现，在SNARE介导的膜和细胞因子运输方面，针对广泛的微生物，突出可以为药物开发提供新途径的差异。此外，由于我们使用SNARE来调查和绘制贩运途径的策略已被证明是如此成功，我们现在将启动一项重大的大规模计划，使用我们开发的检测发现管道（包括活细胞成像）来研究巨噬细胞中所有SNARE介导的贩运途径。这将为许多SNARE（包括与疾病相关的SNARE）提供有价值的信息，并将阐明控制免疫中所有巨噬细胞作用（包括细胞因子分泌和抗原呈递）的运输途径。所有这些途径都与目前临床上使用的或在炎症性疾病中研究的药物靶点以及疫苗的开发高度相关。

Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much acclaimed and novel pathway that allows efficient, combined cytokine secretion and phagocytosis in macrophages. Our studies proposed here will now expand on this discovery by comparing the phagocytic process, in terms of SNARE-mediated membrane and cytokine trafficking, for a wide range of microbes, highlighting differences that could provide new avenues for drug development. Moreover, since our strategy of using SNAREs to investigate and map trafficking pathways has proven so successful, we will now launch a major large-scale initiative to study ALL SNARE-mediated trafficking pathways in macrophages using a discovery pipeline of assays, including live cell imaging, we have developed. This will provide valuable information on many SNAREs including those associated with disease, and will elucidate trafficking pathways governing all macrophage actions in immunity, including cytokine secretion and antigen presentation. All of these pathways are highly relevant to current drug targets being used clinically or studied in inflammatory disease and for the development of vaccines.