PT  - JOURNAL ARTICLE
AU  - Katharina Ernst
AU  - Ann-Katrin Mittler
AU  - Veronika Winkelmann
AU  - Nina Eberhardt
AU  - Anna Anastasia
AU  - Michael Sonnabend
AU  - Robin Lochbaum
AU  - Jan Wirsching
AU  - Ciaran Skerry
AU  - Nicholas H. Carbonetti
AU  - Manfred Frick
AU  - Holger Barth
TI  - Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
AID  - 10.1101/2020.09.24.303321
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.24.303321
4099  - http://biorxiv.org/content/early/2020/09/25/2020.09.24.303321.short
4100  - http://biorxiv.org/content/early/2020/09/25/2020.09.24.303321.full
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.