RT Journal Article SR Electronic T1 Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.09.24.303321 DO 10.1101/2020.09.24.303321 A1 Katharina Ernst A1 Ann-Katrin Mittler A1 Veronika Winkelmann A1 Nina Eberhardt A1 Anna Anastasia A1 Michael Sonnabend A1 Robin Lochbaum A1 Jan Wirsching A1 Ciaran Skerry A1 Nicholas H. Carbonetti A1 Manfred Frick A1 Holger Barth YR 2020 UL http://biorxiv.org/content/early/2020/09/25/2020.09.24.303321.abstract AB 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.Competing Interest StatementThe authors have declared no competing interest.