Macrophages rapidly transfer pathogens from lipid raft vacuoles to autophagosomes
Macrophages rapidly transfer pathogens from lipid raft vacuoles to autophagosomes
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DOI：
10.4161/auto.1.1.1589
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发表时间：
2005-04-01
期刊：
影响因子：
13.3
通讯作者：
Swanson, Michele S.
中科院分区：
文献类型：
--
作者：
Amer, Amal O.;Byrne, Brenda G.;Swanson, Michele S.
巨噬细胞激活自噬是对嗜肺军团菌感染的直接反应，但什么标志着病原体吞噬小体作为自噬机制的目标尚不清楚。由于与内质网相关的各种细菌、寄生虫、病毒和毒素通过胆固醇依赖的途径进入宿主细胞，我们检验了当微生物参与脂筏结构域的组成部分时触发自噬的假设。当胞内呼吸道病原体肺炎杆菌或胞外尿路病原体FimH(+)大肠杆菌通过胆固醇敏感机制进入巨噬细胞时，它们立即停留在富含糖基磷脂酰肌醇部分和自噬酶ATG7的空泡中。与预期的自噬小体一样，空泡依次获得内质网蛋白Bip、自噬标记Atg8和Monodansyl-cadverine以及溶酶体蛋白LAMP-1。巨噬细胞对病原体的强烈反应是依赖于胆固醇的，因为当巨噬细胞被甲基-β-环糊精或菲立磷脂预处理时，观察到较少的富含ATG7的空泡。在该模型中，巨噬细胞利用自噬在脂筏途径中捕获病原体，以在溶酶体中处置之前呈现抗原。
Macrophages activate autophagy as an immediate response to Legionella pneumophila infection, but what marks the pathogen phagosome as a target for the autophagy machinery is not known. Because a variety of bacteria, parasites, viruses, and toxins that associate with the endoplasmic reticulum enter host cells by a cholesterol-dependent route, we tested the hypothesis that autophagy is triggered when microbes engage components of lipid raft domains. As the intracellular respiratory pathogen L. pneumophila or the extracellular uropathogen FimH(+) Escherichia coli entered macrophages by a cholesterol-sensitive mechanism, they immediatezly resided in vacuoles rich in glycosylphosphatidylinositol moieties and the autophagy enzyme Atg7. As expected for autophagosomes, the vacuoles sequentially acquired the endoplasmic reticulum protein BiP, the autophagy markers Atg8 and monodansyl-cadaverine, and the lysosomal protein LAMP-1. A robust macrophage response to the pathogens was cholesterol-dependent, since fewer Atg7-rich vacuoles were observed when macrophages were pretreated with methyl-beta-cyclodextrin or filipin. A model in which macrophages exploit autophagy to capture pathogens within the lipid raft pathway for antigen presentation prior to disposal in lysosomes is discussed.