Naj Xenia, Linder Stefan
Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246 Hamburg, Germany.
Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246 Hamburg, Germany.
Cell Rep. 2015 Sep 22;12(11):1816-30. doi: 10.1016/j.celrep.2015.08.027. Epub 2015 Sep 3.
Borrelia burgdorferi is the causative agent of Lyme disease, a multisystemic disorder affecting the skin, joints, and nervous system. Macrophages and dendritic cells counteract Borrelia dissemination through internalization and degradation of spirochetes. We now show that Borrelia internalization by primary human macrophages involves uptake and compaction into Rab22a-positive phagosomes that are in close contact with Rab5a-positive vesicles. Compaction of borreliae involves membrane extrusion from phagosomes, is driven by Rab22a and Rab5a activity, and is coordinated by ER tubules forming contact sites of Rab22a phagosomes with Rab5a vesicles. Importantly, Rab22a and Rab5a depletion leads to reduced localization to lysosomes and to increased intracellular survival of spirochetes. These data show that Rab22a- and Rab5a-driven phagosomal uptake is a crucial step in the vesicular cascade that leads to elimination of spirochetes by macrophages. Rab22a and Rab5a thus present as potential molecular targets for the modulation of intracellular processing of borreliae in human immune cells.
伯氏疏螺旋体是莱姆病的病原体，莱姆病是一种影响皮肤、关节和神经系统的多系统疾病。巨噬细胞和树突状细胞通过内化和降解螺旋体来对抗伯氏疏螺旋体的传播。我们现在表明，原代人巨噬细胞内化伯氏疏螺旋体涉及摄取并压实到与Rab5a阳性囊泡紧密接触的Rab22a阳性吞噬体中。疏螺旋体的压实涉及从吞噬体挤出膜，由Rab22a和Rab5a活性驱动，并由内质网小管协调，内质网小管形成Rab22a吞噬体与Rab5a囊泡的接触位点。重要的是，Rab22a和Rab5a的缺失导致定位到溶酶体的减少以及螺旋体在细胞内存活的增加。这些数据表明，Rab22a和Rab5a驱动的吞噬体摄取是囊泡级联反应中的关键步骤，该级联反应导致巨噬细胞消除螺旋体。因此，Rab22a和Rab5a是调节人类免疫细胞中疏螺旋体细胞内加工的潜在分子靶点。
