Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1784696885146025984 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9052917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yujia complementdysregulationisassociatedwithseverecovid19illness AT gerbergloriaf complementdysregulationisassociatedwithseverecovid19illness AT chenhang complementdysregulationisassociatedwithseverecovid19illness AT yuanxuan complementdysregulationisassociatedwithseverecovid19illness AT chaturvedishruti complementdysregulationisassociatedwithseverecovid19illness AT braunsteinevanm complementdysregulationisassociatedwithseverecovid19illness AT brodskyroberta complementdysregulationisassociatedwithseverecovid19illness |