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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: Savitt, Anne G., Manimala, Samantha, White, Tiara, Fandaros, Marina, Yin, Wei, Duan, Huiquan, Xu, Xin, Geisbrecht, Brian V., Rubenstein, David A., Kaplan, Allen P., Peerschke, Ellinor I., Ghebrehiwet, Berhane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602850/
https://www.ncbi.nlm.nih.gov/pubmed/34804054
http://dx.doi.org/10.3389/fimmu.2021.767347
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author Savitt, Anne G.
Manimala, Samantha
White, Tiara
Fandaros, Marina
Yin, Wei
Duan, Huiquan
Xu, Xin
Geisbrecht, Brian V.
Rubenstein, David A.
Kaplan, Allen P.
Peerschke, Ellinor I.
Ghebrehiwet, Berhane
author_facet Savitt, Anne G.
Manimala, Samantha
White, Tiara
Fandaros, Marina
Yin, Wei
Duan, Huiquan
Xu, Xin
Geisbrecht, Brian V.
Rubenstein, David A.
Kaplan, Allen P.
Peerschke, Ellinor I.
Ghebrehiwet, Berhane
author_sort Savitt, Anne G.
collection PubMed
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.
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spelling pubmed-86028502021-11-20 SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems Savitt, Anne G. Manimala, Samantha White, Tiara Fandaros, Marina Yin, Wei Duan, Huiquan Xu, Xin Geisbrecht, Brian V. Rubenstein, David A. Kaplan, Allen P. Peerschke, Ellinor I. Ghebrehiwet, Berhane Front Immunol Immunology 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. Frontiers Media S.A. 2021-11-05 /pmc/articles/PMC8602850/ /pubmed/34804054 http://dx.doi.org/10.3389/fimmu.2021.767347 Text en Copyright © 2021 Savitt, Manimala, White, Fandaros, Yin, Duan, Xu, Geisbrecht, Rubenstein, Kaplan, Peerschke and Ghebrehiwet https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Savitt, Anne G.
Manimala, Samantha
White, Tiara
Fandaros, Marina
Yin, Wei
Duan, Huiquan
Xu, Xin
Geisbrecht, Brian V.
Rubenstein, David A.
Kaplan, Allen P.
Peerschke, Ellinor I.
Ghebrehiwet, Berhane
SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems
title 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_short 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
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602850/
https://www.ncbi.nlm.nih.gov/pubmed/34804054
http://dx.doi.org/10.3389/fimmu.2021.767347
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