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.
Highlights
Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit
We recently demonstrated that specific members of the cyclophilin (Cyp) family, namely CypA and Cyp[40] are involved in uptake of PTS1 into the cytosol of target cells[29]
Presence of Rad, cyclosporine A (CsA) or FK506 robustly reduced CHO-K1 cell clustering compared to cells treated with PT (Fig. 1a)
Summary
Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. Whooping cough is a highly transmissible respiratory disease caused by droplet infection of the respiratory tract with Bordetella (B.) pertussis. This bacterium mediates disease through several virulence factors including adhesion factors and the enzymatically active pertussis toxin (PT)[1]. PTS1 covalently transfers ADP-ribose from N AD+ onto the α-subunit of trimeric inhibitory G proteins (Giα)[24,25] This ADP-ribosylation inhibits the activity of Giα as a negative regulator of membrane-bound adenylate cyclase, leading to increased intracellular cAMP levels and disturbed signal transduction
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