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Toxins 2018, 10(5), 181; https://doi.org/10.3390/toxins10050181

Pharmacological Cyclophilin Inhibitors Prevent Intoxication of Mammalian Cells with Bordetella pertussis Toxin

1
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, 89081 Ulm, Germany
2
Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
These Authors contributed equally.
*
Authors to whom correspondence should be addressed.
Received: 9 March 2018 / Revised: 18 April 2018 / Accepted: 23 April 2018 / Published: 1 May 2018
(This article belongs to the Section Bacterial Toxins)
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Abstract

The Bordetella pertussis toxin (PT) is one important virulence factor causing the severe childhood disease whooping cough which still accounted for approximately 63,000 deaths worldwide in children in 2013. PT consists of PTS1, the enzymatically active (A) subunit and a non-covalently linked pentameric binding/transport (B) subunit. After endocytosis, PT takes a retrograde route to the endoplasmic reticulum (ER), where PTS1 is released into the cytosol. In the cytosol, PTS1 ADP-ribosylates inhibitory alpha subunits of trimeric GTP-binding proteins (Giα) leading to increased cAMP levels and disturbed signalling. Here, we show that the cyclophilin (Cyp) isoforms CypA and Cyp40 directly interact with PTS1 in vitro and that Cyp inhibitors cyclosporine A (CsA) and its tailored non-immunosuppressive derivative VK112 both inhibit intoxication of CHO-K1 cells with PT, as analysed in a morphology-based assay. Moreover, in cells treated with PT in the presence of CsA, the amount of ADP-ribosylated Giα was significantly reduced and less PTS1 was detected in the cytosol compared to cells treated with PT only. The results suggest that the uptake of PTS1 into the cytosol requires Cyps. Therefore, CsA/VK112 represent promising candidates for novel therapeutic strategies acting on the toxin level to prevent the severe, life-threatening symptoms caused by PT. View Full-Text
Keywords: pertussis toxin; whooping cough; cellular uptake; membrane transport; cyclosporine A; cyclophilins; chaperones; novel drug targets pertussis toxin; whooping cough; cellular uptake; membrane transport; cyclosporine A; cyclophilins; chaperones; novel drug targets
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Ernst, K.; Eberhardt, N.; Mittler, A.-K.; Sonnabend, M.; Anastasia, A.; Freisinger, S.; Schiene-Fischer, C.; Malešević, M.; Barth, H. Pharmacological Cyclophilin Inhibitors Prevent Intoxication of Mammalian Cells with Bordetella pertussis Toxin. Toxins 2018, 10, 181.

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