Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 03 2021
08 03 2021
Historique:
received:
03
08
2020
accepted:
16
02
2021
entrez:
9
3
2021
pubmed:
10
3
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33686161
doi: 10.1038/s41598-021-84817-2
pii: 10.1038/s41598-021-84817-2
pmc: PMC7940712
doi:
Substances chimiques
Enzyme Inhibitors
0
Molecular Chaperones
0
Pertussis Toxin
EC 2.4.2.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5429Subventions
Organisme : NIAID NIH HHS
ID : R01 AI141372
Pays : United States
Références
Agents Actions. 1976 Jul;6(4):468-75
pubmed: 8969
Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004404
pubmed: 17636756
Anal Chem. 2013 May 7;85(9):4247-50
pubmed: 23560702
Curr Opin Pharmacol. 2019 Aug;47:126-132
pubmed: 31039505
Eur J Cell Biol. 1997 May;73(1):40-8
pubmed: 9174670
Cell. 2007 Oct 5;131(1):121-35
pubmed: 17923092
Front Immunol. 2019 Dec 13;10:2869
pubmed: 31921136
Biochim Biophys Acta. 2015 Oct;1850(10):2005-16
pubmed: 25445709
Biochemistry. 2006 Nov 21;45(46):13734-40
pubmed: 17105192
Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
pubmed: 12563018
Biomolecules. 2018 Dec 14;8(4):
pubmed: 30558250
Cell Microbiol. 2008 May;10(5):1130-9
pubmed: 18201245
Cell Microbiol. 2009 May;11(5):780-95
pubmed: 19159389
Infect Immun. 2008 Nov;76(11):5139-48
pubmed: 18765723
Pediatr Infect Dis. 1984 Sep-Oct;3(5):467-86
pubmed: 6093069
Cell. 1989 Mar 10;56(5):801-13
pubmed: 2647301
Eukaryot Cell. 2005 May;4(5):849-60
pubmed: 15879519
Proc Biol Sci. 2016 Jan 13;283(1822):
pubmed: 26763701
Cell Microbiol. 2012 Aug;14(8):1193-205
pubmed: 22420783
Vaccine. 2011 Mar 16;29(13):2355-6
pubmed: 21129396
Biochemistry. 1982 Oct 26;21(22):5516-22
pubmed: 6293544
Infect Immun. 2014 Oct;82(10):4212-21
pubmed: 25069981
APMIS. 2010 Dec;118(12):968-72
pubmed: 21091778
J Mol Biol. 1996 May 17;258(4):661-71
pubmed: 8637000
Infect Immun. 2016 Nov 18;84(12):3388-3398
pubmed: 27647866
Toxins (Basel). 2018 May 01;10(5):
pubmed: 29723951
J Biol Chem. 2014 Nov 28;289(48):33644-54
pubmed: 25320090
Cell Microbiol. 2019 Oct;21(10):e13074
pubmed: 31231933
Cell Microbiol. 2011 Mar;13(3):359-73
pubmed: 20946244
J Immunol. 1985 Dec;135(6):4135-43
pubmed: 2999238
ACS Sens. 2020 Nov 25;5(11):3438-3448
pubmed: 33147407
J Biol Chem. 2003 Aug 22;278(34):32266-74
pubmed: 12805360
Infect Immun. 1983 Jun;40(3):1198-203
pubmed: 6682833
Infect Immun. 2007 Jun;75(6):2946-53
pubmed: 17420233
Cell Microbiol. 2010 Feb;12(2):233-47
pubmed: 19840027
Structure. 1994 Jan 15;2(1):45-57
pubmed: 8075982
Biomed J. 2013 May-Jun;36(3):106-17
pubmed: 23806880
J Mol Biol. 2015 Mar 27;427(6 Pt A):1224-38
pubmed: 25058685
Clin Microbiol Rev. 2005 Apr;18(2):326-82
pubmed: 15831828
Physiol Rev. 2019 Jan 1;99(1):707-738
pubmed: 30516439
Front Pharmacol. 2018 Nov 13;9:1287
pubmed: 30483129
Pathog Dis. 2016 Aug;74(6):
pubmed: 27369899
Sci Rep. 2017 Apr 4;7(1):613
pubmed: 28377614
J Biol Chem. 1983 Feb 25;258(4):2072-5
pubmed: 6296122
Infect Immun. 2011 Oct;79(10):3913-21
pubmed: 21768281
Infect Immun. 2004 May;72(5):3066-8
pubmed: 15102823
FEBS J. 2011 Dec;278(23):4668-82
pubmed: 21740523
J Biol Chem. 2019 Aug 9;294(32):12122-12131
pubmed: 31221799
Curr Opin Infect Dis. 2016 Jun;29(3):287-94
pubmed: 26906206
ACS Infect Dis. 2020 Apr 10;6(4):588-602
pubmed: 31899865
Antimicrob Agents Chemother. 1994 Aug;38(8):1763-72
pubmed: 7527198
Infect Immun. 1989 Nov;57(11):3324-30
pubmed: 2478471
Sci Rep. 2017 Jun 2;7(1):2724
pubmed: 28578412
Toxins (Basel). 2019 Jun 27;11(7):
pubmed: 31252532
Infect Immun. 2017 Oct 18;85(11):
pubmed: 28784932
Proc Natl Acad Sci U S A. 1982 May;79(10):3129-33
pubmed: 6954463
Sci Rep. 2016 Feb 03;6:20301
pubmed: 26839186
J Clin Invest. 2005 Dec;115(12):3594-601
pubmed: 16294220
Infect Immun. 1995 Mar;63(3):825-32
pubmed: 7868253
Toxins (Basel). 2019 Jul 17;11(7):
pubmed: 31319496
Cell. 2005 Mar 11;120(5):715-27
pubmed: 15766533
Pathog Dis. 2016 Oct;74(7):
pubmed: 27609461
Methods Mol Med. 2005;107:183-206
pubmed: 15492373
Cell. 1991 Aug 23;66(4):807-15
pubmed: 1715244
Pediatrics. 1997 Dec;100(6):E10
pubmed: 9382911
J Biol Chem. 2010 Oct 8;285(41):31261-7
pubmed: 20667832
Curr Top Microbiol Immunol. 2017;406:163-198
pubmed: 27197646
J Biol Chem. 1996 Feb 9;271(6):2961-5
pubmed: 8621687
Am J Respir Crit Care Med. 2019 Mar 15;199(6):715-727
pubmed: 30352166
Clin Microbiol Rev. 2016 Jul;29(3):449-86
pubmed: 27029594
Pathog Dis. 2015 Nov;73(8):ftv073
pubmed: 26394801