A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
Tekijät: 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
Kustantaja: NATURE RESEARCH
Julkaisuvuosi: 2021
Journal: Scientific Reports
Tietokannassa oleva lehden nimi: SCIENTIFIC REPORTS
Lehden akronyymi: SCI REP-UK
Artikkelin numero: ARTN 5429
Vuosikerta: 11
Numero: 1
Sivujen määrä: 17
ISSN: 2045-2322
eISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-021-84817-2
Rinnakkaistallenteen osoite: 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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
