SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2024.1360364/full |
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| author | Christopher J. Hatch Sebastian D. Piombo Jennifer S. Fang Johannes S. Gach Makena L. Ewald William K. Van Trigt Brian G. Coon Brian G. Coon Jay M. Tong Donald N. Forthal Donald N. Forthal Christopher C. W. Hughes Christopher C. W. Hughes |
| author_facet | Christopher J. Hatch Sebastian D. Piombo Jennifer S. Fang Johannes S. Gach Makena L. Ewald William K. Van Trigt Brian G. Coon Brian G. Coon Jay M. Tong Donald N. Forthal Donald N. Forthal Christopher C. W. Hughes Christopher C. W. Hughes |
| author_sort | Christopher J. Hatch |
| collection | DOAJ |
| description | BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia.MethodsThe vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed.ResultsThe VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy.DiscussionOur findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics. |
| first_indexed | 2024-04-24T21:43:35Z |
| format | Article |
| id | doaj.art-5e25787c77e74466b0cead1fdfb7b9f3 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-24T21:43:35Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-5e25787c77e74466b0cead1fdfb7b9f32024-03-21T04:41:17ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2024-03-011110.3389/fcvm.2024.13603641360364SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological systemChristopher J. Hatch0Sebastian D. Piombo1Jennifer S. Fang2Johannes S. Gach3Makena L. Ewald4William K. Van Trigt5Brian G. Coon6Brian G. Coon7Jay M. Tong8Donald N. Forthal9Donald N. Forthal10Christopher C. W. Hughes11Christopher C. W. Hughes12Department of Biomedical Engineering, University of California, Irvine, CA, United StatesDepartment of Pediatrics, School of Medicine, Institute for Clinical and Translational Science, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesDivision of Infectious Diseases, School of Medicine, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesCardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesDepartment of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United StatesDepartment of Biomedical Engineering, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesDivision of Infectious Diseases, School of Medicine, University of California, Irvine, CA, United StatesDepartment of Biomedical Engineering, University of California, Irvine, CA, United StatesDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA, United StatesBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia.MethodsThe vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed.ResultsThe VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy.DiscussionOur findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics.https://www.frontiersin.org/articles/10.3389/fcvm.2024.1360364/fullCOVID-19endothelial dysfunctionhypercytokinemiamicrophysiological systemsshear stress |
| spellingShingle | Christopher J. Hatch Sebastian D. Piombo Jennifer S. Fang Johannes S. Gach Makena L. Ewald William K. Van Trigt Brian G. Coon Brian G. Coon Jay M. Tong Donald N. Forthal Donald N. Forthal Christopher C. W. Hughes Christopher C. W. Hughes SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system Frontiers in Cardiovascular Medicine COVID-19 endothelial dysfunction hypercytokinemia microphysiological systems shear stress |
| title | SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system |
| title_full | SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system |
| title_fullStr | SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system |
| title_full_unstemmed | SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system |
| title_short | SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system |
| title_sort | sars cov 2 infection of endothelial cells dependent on flow induced ace2 expression drives hypercytokinemia in a vascularized microphysiological system |
| topic | COVID-19 endothelial dysfunction hypercytokinemia microphysiological systems shear stress |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2024.1360364/full |
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