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

Abstract

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, 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.

• Authors: Katharina Ernst, Ann-Katrin Mittler, Veronika Winkelmann, Carolin Kling, Nina Eberhardt, Anna Anastasia, Michael Sonnabend, Robin Lochbaum, Jan Wirsching, Moona Sakari, Arto T Pulliainen, Ciaran Skerry, Nicholas H Carbonetti, Manfred Frick, Holger Barth
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 5429 (03 08 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33686161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Molecular Chaperones
• Pertussis Toxin

Topics

• Animals
• Bordetella pertussis (enzymology, metabolism, pathogenicity)
• CHO Cells
• Cricetulus
• Drug Delivery Systems
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (metabolism, microbiology)
• HEK293 Cells
• Humans
• Leukocytosis (chemically induced, drug therapy, metabolism)
• Mice
• Molecular Chaperones (antagonists & inhibitors, genetics, metabolism)
• Pertussis Toxin (toxicity)