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Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection
Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epitheli...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Thoracic Society
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399142/ https://www.ncbi.nlm.nih.gov/pubmed/37071849 http://dx.doi.org/10.1165/rcmb.2022-0373OC |
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author | Zhang, Hui Gerasimovskaya, Evgenia McCarthy, Mary K. May, Nicholas A. Prasad, Ram Raj Riddle, Suzette McKeon, B. Alexandre Kumar, Sushil Li, Min Hu, Cheng-Jun Frid, Maria G. Morrison, Thomas E. Stenmark, Kurt R. |
author_facet | Zhang, Hui Gerasimovskaya, Evgenia McCarthy, Mary K. May, Nicholas A. Prasad, Ram Raj Riddle, Suzette McKeon, B. Alexandre Kumar, Sushil Li, Min Hu, Cheng-Jun Frid, Maria G. Morrison, Thomas E. Stenmark, Kurt R. |
author_sort | Zhang, Hui |
collection | PubMed |
description | Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2–infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2–infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2–infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells. |
format | Online Article Text |
id | pubmed-10399142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Thoracic Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-103991422023-08-04 Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection Zhang, Hui Gerasimovskaya, Evgenia McCarthy, Mary K. May, Nicholas A. Prasad, Ram Raj Riddle, Suzette McKeon, B. Alexandre Kumar, Sushil Li, Min Hu, Cheng-Jun Frid, Maria G. Morrison, Thomas E. Stenmark, Kurt R. Am J Respir Cell Mol Biol Original Research Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2–infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2–infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2–infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells. American Thoracic Society 2023-04-18 /pmc/articles/PMC10399142/ /pubmed/37071849 http://dx.doi.org/10.1165/rcmb.2022-0373OC Text en Copyright © 2023 by the American Thoracic Society https://creativecommons.org/licenses/by/4.0/This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) . For commercial usage and reprints, please e-mail Diane Gern. |
spellingShingle | Original Research Zhang, Hui Gerasimovskaya, Evgenia McCarthy, Mary K. May, Nicholas A. Prasad, Ram Raj Riddle, Suzette McKeon, B. Alexandre Kumar, Sushil Li, Min Hu, Cheng-Jun Frid, Maria G. Morrison, Thomas E. Stenmark, Kurt R. Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection |
title | Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection |
title_full | Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection |
title_fullStr | Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection |
title_full_unstemmed | Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection |
title_short | Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection |
title_sort | local complement contributes to pathogenic activation of lung endothelial cells in sars-cov-2 infection |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399142/ https://www.ncbi.nlm.nih.gov/pubmed/37071849 http://dx.doi.org/10.1165/rcmb.2022-0373OC |
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