SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems.
COVID-19
Sars-CoV-2
bradykinin
complement
kinin-kallikrein system
post COVID “long-haulers”
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
30
08
2021
accepted:
19
10
2021
entrez:
22
11
2021
pubmed:
23
11
2021
medline:
27
11
2021
Statut:
epublish
Résumé
Infection with SARS-CoV-2 triggers the simultaneous activation of innate inflammatory pathways including the complement system and the kallikrein-kinin system (KKS) generating in the process potent vasoactive peptides that contribute to severe acute respiratory syndrome (SARS) and multi-organ failure. The genome of SARS-CoV-2 encodes four major structural proteins - the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. However, the role of these proteins in either binding to or activation of the complement system and/or the KKS is still incompletely understood. In these studies, we used: solid phase ELISA, hemolytic assay and surface plasmon resonance (SPR) techniques to examine if recombinant proteins corresponding to S1, N, M and E: (a) bind to C1q, gC1qR, FXII and high molecular weight kininogen (HK), and (b) activate complement and/or the KKS. Our data show that the viral proteins: (a) bind C1q and activate the classical pathway of complement, (b) bind FXII and HK, and activate the KKS in normal human plasma to generate bradykinin and (c) bind to gC1qR, the receptor for the globular heads of C1q (gC1q) which in turn could serve as a platform for the activation of both the complement system and KKS. Collectively, our data indicate that the SARS-CoV-2 viral particle can independently activate major innate inflammatory pathways for maximal damage and efficiency. Therefore, if efficient therapeutic modalities for the treatment of COVID-19 are to be designed, a strategy that includes blockade of the four major structural proteins may provide the best option.
Identifiants
pubmed: 34804054
doi: 10.3389/fimmu.2021.767347
pmc: PMC8602850
doi:
Substances chimiques
Antigens, Viral
0
C1QBP protein, human
0
Carrier Proteins
0
Mitochondrial Proteins
0
Recombinant Proteins
0
Viral Structural Proteins
0
Complement System Proteins
9007-36-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
767347Subventions
Organisme : NIAID NIH HHS
ID : R56 AI122376
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121511
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI084178
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI060866
Pays : United States
Informations de copyright
Copyright © 2021 Savitt, Manimala, White, Fandaros, Yin, Duan, Xu, Geisbrecht, Rubenstein, Kaplan, Peerschke and Ghebrehiwet.
Déclaration de conflit d'intérêts
BG and EP receive royalties from the sale of anti-gC1qR mAbs and gC1qR detection assay kit. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.
Références
Immunobiology. 1998 Aug;199(2):239-49
pubmed: 9777409
J Immunol. 2014 Jan 1;192(1):377-84
pubmed: 24319267
Nat Med. 2020 Oct;26(10):1609-1615
pubmed: 32747830
Nat Rev Immunol. 2020 Jun;20(6):343-344
pubmed: 32327719
J Immunol. 2001 Nov 1;167(9):5264-72
pubmed: 11673541
Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):25018-25025
pubmed: 32943538
Front Immunol. 2011 Nov 1;2:
pubmed: 22282702
Hybridoma. 1996 Oct;15(5):333-42
pubmed: 8913782
Front Immunol. 2020 Jul 07;11:1661
pubmed: 32733489
mBio. 2013 Aug 06;4(4):
pubmed: 23919993
J Exp Med. 1971 Apr 1;133(4):696-712
pubmed: 4251126
Adv Virus Res. 2005;64:165-230
pubmed: 16139595
Thromb Haemost. 2004 Jan;91(1):61-70
pubmed: 14691569
Mod Pathol. 2005 Jan;18(1):1-10
pubmed: 15272286
Clin Immunol. 2020 Jun;215:108450
pubmed: 32360516
Kidney Int. 2020 Aug;98(2):314-322
pubmed: 32461141
Oncotarget. 2017 Feb 21;8(8):12686-12694
pubmed: 27050368
Semin Immunol. 2019 Oct;45:101338
pubmed: 31744753
Immunol Rev. 2001 Apr;180:56-64
pubmed: 11414364
Viruses. 2014 Aug 07;6(8):2991-3018
pubmed: 25105276
Thromb Haemost. 2004 Oct;92(4):811-9
pubmed: 15467913
Virol J. 2019 May 27;16(1):69
pubmed: 31133031
Mol Immunol. 2016 Jun;74:18-26
pubmed: 27111569
J Virol. 1994 Oct;68(10):6523-34
pubmed: 8083990
Elife. 2020 Jul 07;9:
pubmed: 32633718
Adv Exp Med Biol. 2006;586:95-105
pubmed: 16893067
Blood. 2020 Oct 29;136(18):2080-2089
pubmed: 32877502
Virus Res. 2016 Jul 15;220:21-32
pubmed: 27063333
Virus Res. 2002 May 10;85(2):151-61
pubmed: 12034482
Virology. 2008 Nov 25;381(2):178-83
pubmed: 18834607
Adv Virus Res. 2006;66:193-292
pubmed: 16877062
Mol Immunol. 2010 Aug;47(13):2161-9
pubmed: 20580091
J Clin Invest. 2020 Nov 2;130(11):5674-5676
pubmed: 32925166
J Clin Invest. 2020 Nov 2;130(11):6151-6157
pubmed: 32759504
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8552-7
pubmed: 8710908
Hum Pathol. 2003 Aug;34(8):743-8
pubmed: 14506633
Mol Immunol. 2010 Aug;47(13):2170-5
pubmed: 20621693
J Allergy Clin Immunol. 2021 Feb;147(2):507-509
pubmed: 33129885
Nat Rev Microbiol. 2019 Mar;17(3):181-192
pubmed: 30531947
Science. 2005 Sep 16;309(5742):1864-8
pubmed: 16166518
J Exp Med. 1994 Jun 1;179(6):1809-21
pubmed: 8195709
J Infect Dis. 2005 May 15;191(10):1697-704
pubmed: 15838797
Eur Respir J. 2020 Jul 30;56(1):
pubmed: 32554532
Front Immunol. 2019 Aug 27;10:2046
pubmed: 31507620
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1530-5
pubmed: 19164550
Mol Immunol. 2002 Sep;39(1-2):69-75
pubmed: 12213329
J Intensive Care. 2020 Jul 10;8:49
pubmed: 32665858
J Virol. 2013 Sep;87(17):9754-67
pubmed: 23824792
J Transl Med. 2014 Oct 05;12:286
pubmed: 25288439
Virology. 1997 Sep 15;236(1):18-29
pubmed: 9299613
Blood. 2020 Oct 1;136(14):1685-1697
pubmed: 32559765
Front Oncol. 2020 Sep 30;10:575854
pubmed: 33102234
Adv Exp Med Biol. 2008;632:81-91
pubmed: 19025116
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Methods Mol Biol. 2015;1282:1-23
pubmed: 25720466
Lancet. 2003 May 24;361(9371):1773-8
pubmed: 12781536
Cell Mol Gastroenterol Hepatol. 2021;12(1):229-250
pubmed: 33515804