A1 Refereed original research article in a scientific journal
Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
Authors: 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
Publication year: 2021
Journal: Scientific Reports
Journal name in source: SCIENTIFIC REPORTS
Journal acronym: SCI REP-UK
Article number: ARTN 5429
Volume: 11
Issue: 1
Number of pages: 17
ISSN: 2045-2322
eISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-021-84817-2
Self-archived copy’s web address: 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.
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