SNARE-mediated protein trafficking in macrophages

巨噬细胞是一种白细胞，通过吞噬或吞噬微生物而引发炎症反应，并通过释放可溶性信使(细胞因子)来招募其他免疫细胞，从而提供一线防御感染的能力。这些防御功能需要巨噬细胞内广泛的蛋白质运输。蛋白质的运输部分是由一系列被称为SNARES的膜融合蛋白来协调的。通过定义相关的陷阱，我们最近发现了一种备受赞誉的新途径，它允许巨噬细胞高效、结合地分泌细胞因子和吞噬细胞。我们在这里提出的研究将在这一发现的基础上进行扩展，通过比较多种微生物在诱捕介导的膜和细胞因子运输方面的吞噬过程，突出可能为药物开发提供新途径的差异。此外，由于我们使用圈套调查和绘制贩运路径的战略已被证明是如此成功，我们现在将发起一项重大的大规模倡议，利用我们开发的包括活细胞成像在内的一系列分析方法来研究所有圈套介导的巨噬细胞运输途径。这将提供许多陷阱的有价值的信息，包括那些与疾病相关的陷阱，并将阐明控制免疫中所有巨噬细胞活动的运输途径，包括细胞因子分泌和抗原递呈。所有这些途径都与目前用于临床或研究炎症性疾病的药物靶点高度相关，并与疫苗的开发密切相关。

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.