Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry.
SARS-CoV-2
anticoagulants
biochemistry
chemical biology
coagulopathy
coronavirus
factor Xa
human
infectious disease
microbiology
nafamostat
viruses
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
23 03 2022
23 03 2022
Historique:
received:
08
02
2022
accepted:
22
02
2022
pubmed:
17
3
2022
medline:
5
4
2022
entrez:
16
3
2022
Statut:
epublish
Résumé
Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases and coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.
Identifiants
pubmed: 35294338
doi: 10.7554/eLife.77444
pii: 77444
pmc: PMC8942469
doi:
pii:
Substances chimiques
Blood Coagulation Factors
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R35 CA197588
Pays : United States
Organisme : NIH HHS
ID : R01AI35270
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2022, Kastenhuber et al.
Déclaration de conflit d'intérêts
EK, MM, BN, JJ, JJ, FM, YW, YB, VC, GW, Bt No competing interests declared, RS is on the scientific advisory board for Miromatrix Inc and is a consultant and speaker for Alnylam Inc, LC is a founder and member of the SAB of Agios Pharmaceuticals and a founder and former member of the SAB of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals). These companies are developing novel therapies for cancer. Holds equity in Agios. Lewis Cantley's laboratory also received some financial support from Ravenna Pharmaceuticals
Références
Int J Artif Organs. 2015 Nov;38(11):595-9
pubmed: 26728787
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5871-6
pubmed: 19321428
Semin Thromb Hemost. 2001;27(2):161-7
pubmed: 11372771
Stroke. 2020 Jul;51(7):2219-2223
pubmed: 32466735
Antiviral Res. 2015 Apr;116:76-84
pubmed: 25666761
Phys Biol. 2013 Jun;10(3):036003
pubmed: 23585459
Lancet. 2021 Jun 12;397(10291):2253-2263
pubmed: 34097856
ACS Infect Dis. 2021 Feb 12;7(2):264-272
pubmed: 33432808
Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620936776
pubmed: 32687449
Elife. 2020 Oct 28;9:
pubmed: 33112236
J Biol Chem. 1998 Feb 20;273(8):4378-86
pubmed: 9468488
N Engl J Med. 2021 Feb 11;384(6):497-511
pubmed: 33264556
PLoS One. 2017 Mar 30;12(3):e0174827
pubmed: 28358853
AIDS Rev. 2021 Feb 08;23(1):40-47
pubmed: 33556957
Toxicon. 2010 Nov;56(6):1007-17
pubmed: 20638400
Cell Res. 2020 Dec;30(12):1059-1060
pubmed: 33139926
Thromb Haemost. 1996 Mar;75(3):503-9
pubmed: 8701416
Blood. 2011 Feb 3;117(5):1710-8
pubmed: 21131592
Trials. 2019 Aug 14;20(1):501
pubmed: 31412955
Am J Hematol. 2020 Dec;95(12):1522-1530
pubmed: 32833259
J Clin Invest. 2019 Jul 2;129(10):4180-4193
pubmed: 31265436
Biochem Biophys Res Commun. 2007 Jul 20;359(1):174-9
pubmed: 17533109
J Exp Med. 2020 Nov 2;217(11):
pubmed: 32692348
Clin Microbiol Rev. 2007 Oct;20(4):660-94
pubmed: 17934078
Sci Signal. 2021 Jan 12;14(665):
pubmed: 33436497
PLoS Pathog. 2021 Jan 25;17(1):e1009246
pubmed: 33493182
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
Nature. 2021 Mar;591(7849):293-299
pubmed: 33494095
J Vis Exp. 2019 Jan 9;(143):
pubmed: 30688313
Adv Enzyme Regul. 1996;36:325-47
pubmed: 8869754
Lancet. 2020 Mar 28;395(10229):1054-1062
pubmed: 32171076
J Mol Biol. 2020 May 1;432(10):3309-3325
pubmed: 32320687
Clin Appl Thromb Hemost. 2009 Sep-Oct;15 Suppl 1:9S-16S
pubmed: 19696042
Cell. 2020 Apr 16;181(2):281-292.e6
pubmed: 32155444
Sci Immunol. 2020 May 13;5(47):
pubmed: 32404436
Vaccines (Basel). 2020 Dec 30;9(1):
pubmed: 33396832
J Clin Pharmacol. 2006 Jan;46(1):37-44
pubmed: 16397282
Int J Nurs Stud. 2021 Feb;114:103854
pubmed: 33326864
J Exp Med. 2021 Mar 1;218(3):
pubmed: 33433624
Nature. 2013 Nov 28;503(7477):535-8
pubmed: 24172901
Nat Cell Biol. 2017 May;19(5):542-549
pubmed: 28436965
Surgery. 2001 Aug;130(2):175-81
pubmed: 11490346
Blood Adv. 2021 Feb 9;5(3):872-888
pubmed: 33560401
Am J Surg. 1996 Apr;171(4):394-8
pubmed: 8604829
Ther Adv Neurol Disord. 2020 Dec 8;13:1756286420978004
pubmed: 33343709
Lancet Rheumatol. 2020 Jul;2(7):e437-e445
pubmed: 32835247
Cell Metab. 2021 Aug 3;33(8):1577-1591.e7
pubmed: 34081913
Stroke. 2020 Jul;51(7):2002-2011
pubmed: 32432996
BMJ. 2020 Dec 15;371:m4750
pubmed: 33323376
Front Pharmacol. 2021 Jul 05;12:708665
pubmed: 34290613
J Virol. 2009 Aug;83(15):7411-21
pubmed: 19439480
J Virol. 2011 May;85(9):4122-34
pubmed: 21325420
Cell Stem Cell. 2012 Apr 6;10(4):385-97
pubmed: 22482504
Nat Biotechnol. 2014 Jan;32(1):84-91
pubmed: 24291815
Virology. 2020 Apr;543:43-53
pubmed: 32056846
N Engl J Med. 2021 Feb 4;384(5):403-416
pubmed: 33378609
Nat Rev Rheumatol. 2020 Oct;16(10):581-589
pubmed: 32733003
J Med Chem. 2019 Jan 24;62(2):480-490
pubmed: 30571119
Nature. 2021 Apr;592(7855):616-622
pubmed: 33567448
Nat Struct Mol Biol. 2020 Aug;27(8):763-767
pubmed: 32647346
J Biol Chem. 2010 Jul 23;285(30):22758-63
pubmed: 20507992
Biochim Biophys Acta. 1981 Oct 13;661(2):342-5
pubmed: 6271224
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
PLoS One. 2009 Nov 17;4(11):e7870
pubmed: 19924243
Nature. 2020 Dec;588(7837):327-330
pubmed: 32942285
J Virol. 2020 Feb 14;94(5):
pubmed: 31801868
Nephron. 1993;64(3):376-81
pubmed: 8341382
iScience. 2020 Jun 26;23(6):101212
pubmed: 32512386
Int J Artif Organs. 2016 Jan;39(1):16-21
pubmed: 26868216
Vasc Health Risk Manag. 2017 Aug 23;13:325-342
pubmed: 28860793
Lancet. 2020 Feb 15;395(10223):497-506
pubmed: 31986264
Sci Transl Med. 2020 Nov 18;12(570):
pubmed: 33139519
EBioMedicine. 2021 Mar;65:103255
pubmed: 33676899
EMBO J. 1990 Dec;9(12):4189-95
pubmed: 2174359
Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12543-7
pubmed: 16116101
Glob Public Health. 2021 Mar;16(3):319-339
pubmed: 33317389
Nat Med. 2015 Dec;21(12):1508-13
pubmed: 26552008
mBio. 2021 Mar 2;12(2):
pubmed: 33653892
J Virol. 2019 Mar 5;93(6):
pubmed: 30626688
Nat Commun. 2020 Mar 27;11(1):1620
pubmed: 32221306
Science. 2020 Jul 17;369(6501):330-333
pubmed: 32366695
PLoS One. 2012;7(1):e29178
pubmed: 22247769
J Virol. 2018 Feb 26;92(6):
pubmed: 29321328
Nature. 2021 Jan;589(7841):270-275
pubmed: 33116299
Am Heart J. 2021 May;235:12-23
pubmed: 33577800
Blood. 2013 Dec 12;122(25):4094-106
pubmed: 24159172
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15214-9
pubmed: 25288733
J Exp Med. 2019 Mar 4;216(3):674-687
pubmed: 30737256
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Antimicrob Agents Chemother. 2020 May 21;64(6):
pubmed: 32312781
J Infect Dis. 2003 Dec 1;188(11):1618-29
pubmed: 14639531
Toxicon. 2013 Feb;62:3-18
pubmed: 23000249
N Engl J Med. 2020 Dec 31;383(27):2603-2615
pubmed: 33301246
J Am Heart Assoc. 2020 Jul 7;9(13):e017559
pubmed: 32538234
Life Sci Alliance. 2020 Jul 23;3(9):
pubmed: 32703818
Gastroenterology. 2020 May;158(6):1831-1833.e3
pubmed: 32142773