SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems

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 failur...

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Autores principales:	Anne G. Savitt, Samantha Manimala, Tiara White, Marina Fandaros, Wei Yin, Huiquan Duan, Xin Xu, Brian V. Geisbrecht, David A. Rubenstein, Allen P. Kaplan, Ellinor I. Peerschke, Berhane Ghebrehiwet
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Sars-CoV-2 complement bradykinin COVID-19 kinin-kallikrein system post COVID “long-haulers” Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/6770e2f74e8948b8a62d2b8fa28fe7c4
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spelling	oai:doaj.org-article:6770e2f74e8948b8a62d2b8fa28fe7c42021-11-05T12:50:28ZSARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems1664-322410.3389/fimmu.2021.767347https://doaj.org/article/6770e2f74e8948b8a62d2b8fa28fe7c42021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.767347/fullhttps://doaj.org/toc/1664-3224Infection 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.Anne G. SavittAnne G. SavittSamantha ManimalaTiara WhiteTiara WhiteMarina FandarosWei YinHuiquan DuanXin XuBrian V. GeisbrechtDavid A. RubensteinAllen P. KaplanEllinor I. PeerschkeBerhane GhebrehiwetFrontiers Media S.A.articleSars-CoV-2complementbradykininCOVID-19kinin-kallikrein systempost COVID “long-haulers”Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Sars-CoV-2 complement bradykinin COVID-19 kinin-kallikrein system post COVID “long-haulers” Immunologic diseases. Allergy RC581-607
spellingShingle	Sars-CoV-2 complement bradykinin COVID-19 kinin-kallikrein system post COVID “long-haulers” Immunologic diseases. Allergy RC581-607 Anne G. Savitt Anne G. Savitt Samantha Manimala Tiara White Tiara White Marina Fandaros Wei Yin Huiquan Duan Xin Xu Brian V. Geisbrecht David A. Rubenstein Allen P. Kaplan Ellinor I. Peerschke Berhane Ghebrehiwet SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
description	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.
format	article
author	Anne G. Savitt Anne G. Savitt Samantha Manimala Tiara White Tiara White Marina Fandaros Wei Yin Huiquan Duan Xin Xu Brian V. Geisbrecht David A. Rubenstein Allen P. Kaplan Ellinor I. Peerschke Berhane Ghebrehiwet
author_facet	Anne G. Savitt Anne G. Savitt Samantha Manimala Tiara White Tiara White Marina Fandaros Wei Yin Huiquan Duan Xin Xu Brian V. Geisbrecht David A. Rubenstein Allen P. Kaplan Ellinor I. Peerschke Berhane Ghebrehiwet
author_sort	Anne G. Savitt
title	SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
title_short	SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
title_full	SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
title_fullStr	SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
title_full_unstemmed	SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
title_sort	sars-cov-2 exacerbates covid-19 pathology through activation of the complement and kinin systems
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/6770e2f74e8948b8a62d2b8fa28fe7c4
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SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems

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