Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

: Ernst Katharina, Mittler Ann-Katrin, Winkelmann Veronika, Kling Carolin, Eberhardt Nina, Anastasia Anna, Sonnabend Michael, Lochbaum Robin, Wirsching Jan, Sakari Moona, Pulliainen Arto T, Skerry Ciaran, Carbonetti Nicholas H, Frick Manfred, Barth Holger

Publisher: NATURE RESEARCH

: 2021

: Scientific Reports

: SCIENTIFIC REPORTS

: SCI REP-UK

: ARTN 5429

: 11

: 1

: 17

: 2045-2322

DOI: https://doi.org/10.1038/s41598-021-84817-2

: https://research.utu.fi/converis/portal/detail/Publication/54714127

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.

s41598-021-84817-2.pdf