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Complement dysregulation is associated with severe COVID-19 illness

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of...

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Autores principales: Yu, Jia, Gerber, Gloria F., Chen, Hang, Yuan, Xuan, Chaturvedi, Shruti, Braunstein, Evan M., Brodsky, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052917/
https://www.ncbi.nlm.nih.gov/pubmed/34289657
http://dx.doi.org/10.3324/haematol.2021.279155
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author Yu, Jia
Gerber, Gloria F.
Chen, Hang
Yuan, Xuan
Chaturvedi, Shruti
Braunstein, Evan M.
Brodsky, Robert A.
author_facet Yu, Jia
Gerber, Gloria F.
Chen, Hang
Yuan, Xuan
Chaturvedi, Shruti
Braunstein, Evan M.
Brodsky, Robert A.
author_sort Yu, Jia
collection PubMed
description Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complementmediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell surface. A positive modified Ham assay (>20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplification induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, suggesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dysregulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity.
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spelling pubmed-90529172022-05-13 Complement dysregulation is associated with severe COVID-19 illness Yu, Jia Gerber, Gloria F. Chen, Hang Yuan, Xuan Chaturvedi, Shruti Braunstein, Evan M. Brodsky, Robert A. Haematologica Article Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complementmediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell surface. A positive modified Ham assay (>20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplification induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, suggesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dysregulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity. Fondazione Ferrata Storti 2021-07-22 /pmc/articles/PMC9052917/ /pubmed/34289657 http://dx.doi.org/10.3324/haematol.2021.279155 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Yu, Jia
Gerber, Gloria F.
Chen, Hang
Yuan, Xuan
Chaturvedi, Shruti
Braunstein, Evan M.
Brodsky, Robert A.
Complement dysregulation is associated with severe COVID-19 illness
title Complement dysregulation is associated with severe COVID-19 illness
title_full Complement dysregulation is associated with severe COVID-19 illness
title_fullStr Complement dysregulation is associated with severe COVID-19 illness
title_full_unstemmed Complement dysregulation is associated with severe COVID-19 illness
title_short Complement dysregulation is associated with severe COVID-19 illness
title_sort complement dysregulation is associated with severe covid-19 illness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052917/
https://www.ncbi.nlm.nih.gov/pubmed/34289657
http://dx.doi.org/10.3324/haematol.2021.279155
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