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 A...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ffe6325e744642199e112ed599bf0f26
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spelling	oai:doaj.org-article:ffe6325e744642199e112ed599bf0f262021-12-02T15:53:59ZPharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo10.1038/s41598-021-84817-22045-2322https://doaj.org/article/ffe6325e744642199e112ed599bf0f262021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84817-2https://doaj.org/toc/2045-2322Abstract 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.Katharina ErnstAnn-Katrin MittlerVeronika WinkelmannCarolin KlingNina EberhardtAnna AnastasiaMichael SonnabendRobin LochbaumJan WirschingMoona SakariArto T. PulliainenCiaran SkerryNicholas H. CarbonettiManfred FrickHolger BarthNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
description	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.
format	article
author	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
author_facet	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
author_sort	Katharina Ernst
title	Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
title_short	Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
title_full	Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
title_fullStr	Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
title_full_unstemmed	Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
title_sort	pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ffe6325e744642199e112ed599bf0f26
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_version_	1718385489309859840

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

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