Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
Lochbaum Robin; Wirsching Jan; Kling Carolin; Pulliainen Arto T; Mittler Ann-Katrin; Sakari Moona; Winkelmann Veronika; Ernst Katharina; Carbonetti Nicholas H; Barth Holger; Frick Manfred; Anastasia Anna; Sonnabend Michael; Eberhardt Nina; Skerry Ciaran
Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
Lochbaum Robin
Wirsching Jan
Kling Carolin
Pulliainen Arto T
Mittler Ann-Katrin
Sakari Moona
Winkelmann Veronika
Ernst Katharina
Carbonetti Nicholas H
Barth Holger
Frick Manfred
Anastasia Anna
Sonnabend Michael
Eberhardt Nina
Skerry Ciaran
NATURE RESEARCH
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021093048848
https://urn.fi/URN:NBN:fi-fe2021093048848
Tiivistelmä
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 alpha -subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. 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 intracellular 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.
Kokoelmat
- Rinnakkaistallenteet [19207]