Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, the role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is characterized in detail. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing cytosolic PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.

中文翻译：

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宿主伴侣的药理靶向作用可在体内和体外保护免受百日咳毒素的侵害

百日咳是由百日咳博德特氏菌引起的，百日咳博德特氏菌释放百日咳毒素（PT），其中包含酶A亚基PTS1和结合/转运B亚基。受体介导的内吞作用后，PT到达内质网，未折叠的PTS1从那里被转运到细胞质。PTS1 ADP-核糖基化G蛋白α亚基，导致cAMP信号转导增加。在这里，详细介绍了目标细胞伴侣Hsp90，Hsp70，亲环蛋白和FK506结合蛋白对胞质PTS1摄取的作用。PTS1在体外和细胞中与伴侣分子特异性且直接相互作用。特定的药理伴侣抑制作用可通过减少细胞内PTS1的含量而保护CHO-K1，人原代气道基底细胞和完全分化的气道上皮免于PT中毒，而不会影响细胞结合或酶活性。PT被人的呼吸道上皮分泌所内化，但未被纤毛细胞内化，并导致顶表面液的增加。亲环素抑制剂在百日咳婴儿小鼠模型中减少了白细胞增多，表明它们有望开发出针对百日咳的新型治疗策略的潜力。