SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells
Abstract SARS-CoV-2 is a viral infection, best studied in the context of epithelial cell infection. Epithelial cells, when infected with SARS-CoV-2 express the viral S-protein, which causes host cells to fuse together into large multi-nucleated cells known as syncytia. Because SARS-CoV-2 infections...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-86242-1 |
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| author | Katie V. Tieu Madaline Espey Aarthi Narayanan Rebecca L. Heise Farhang Alem Daniel E. Conway |
| author_facet | Katie V. Tieu Madaline Espey Aarthi Narayanan Rebecca L. Heise Farhang Alem Daniel E. Conway |
| author_sort | Katie V. Tieu |
| collection | DOAJ |
| description | Abstract SARS-CoV-2 is a viral infection, best studied in the context of epithelial cell infection. Epithelial cells, when infected with SARS-CoV-2 express the viral S-protein, which causes host cells to fuse together into large multi-nucleated cells known as syncytia. Because SARS-CoV-2 infections also frequently present with cardiovascular phenotypes, we sought to understand if S-protein expression would also result in syncytia formation in endothelial cells. S-protein expression in endothelial cells was sufficient to induce the formation of multi-nucleated cells, with an average of 10% of all cells forming syncytia with an average of 6 nuclei per syncytia after 72 h of S-protein expression. Formation of syncytia was associated with the formation of gaps between cells, suggesting the potential for syncytia formation to compromise barrier function. Inhibition of myosin light chain kinase (MLCK), but not Rho-associated protein kinase, inhibited the formation of syncytia, suggesting a role for MLCK in syncytia formation. Further supporting the role of cellular contractility in syncytia formation, we also observed a reduction in the occurrence of syncytia for endothelial cells grown on substrates with reduced stiffness. Because endothelial cells are exposed to physiological forces due to blood flow, we examined the effects of cyclic biaxial stretch and fluid shear stress. While biaxial stretch did not affect syncytia formation, endothelial cells exposed to fluid shear stress were more resistant to syncytia formation. Finally, we observed that endothelial cells are suitable host cells for SARS-CoV-2 viral infection and replication, and that viral infection also causes syncytia formation. Our studies indicate that endothelial cells, in addition to epithelial cells, should also be considered a target for SARS-CoV-2 infection and a driver of COVID-19-associated pathology. |
| format | Article |
| id | doaj-art-e7a332f4716242d39d92205ad3250e5f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-e7a332f4716242d39d92205ad3250e5f2025-02-02T12:16:23ZengNature PortfolioScientific Reports2045-23222025-01-0115111010.1038/s41598-025-86242-1SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cellsKatie V. Tieu0Madaline Espey1Aarthi Narayanan2Rebecca L. Heise3Farhang Alem4Daniel E. Conway5Department of Biomedical Engineering, The Ohio State UniversityDepartment of Biomedical Engineering, Virginia Commonwealth UniversityDepartment of Biology, George Mason UniversityDepartment of Biomedical Engineering, Virginia Commonwealth UniversitySchool of Systems Biology, George Mason UniversityDepartment of Biomedical Engineering, The Ohio State UniversityAbstract SARS-CoV-2 is a viral infection, best studied in the context of epithelial cell infection. Epithelial cells, when infected with SARS-CoV-2 express the viral S-protein, which causes host cells to fuse together into large multi-nucleated cells known as syncytia. Because SARS-CoV-2 infections also frequently present with cardiovascular phenotypes, we sought to understand if S-protein expression would also result in syncytia formation in endothelial cells. S-protein expression in endothelial cells was sufficient to induce the formation of multi-nucleated cells, with an average of 10% of all cells forming syncytia with an average of 6 nuclei per syncytia after 72 h of S-protein expression. Formation of syncytia was associated with the formation of gaps between cells, suggesting the potential for syncytia formation to compromise barrier function. Inhibition of myosin light chain kinase (MLCK), but not Rho-associated protein kinase, inhibited the formation of syncytia, suggesting a role for MLCK in syncytia formation. Further supporting the role of cellular contractility in syncytia formation, we also observed a reduction in the occurrence of syncytia for endothelial cells grown on substrates with reduced stiffness. Because endothelial cells are exposed to physiological forces due to blood flow, we examined the effects of cyclic biaxial stretch and fluid shear stress. While biaxial stretch did not affect syncytia formation, endothelial cells exposed to fluid shear stress were more resistant to syncytia formation. Finally, we observed that endothelial cells are suitable host cells for SARS-CoV-2 viral infection and replication, and that viral infection also causes syncytia formation. Our studies indicate that endothelial cells, in addition to epithelial cells, should also be considered a target for SARS-CoV-2 infection and a driver of COVID-19-associated pathology.https://doi.org/10.1038/s41598-025-86242-1 |
| spellingShingle | Katie V. Tieu Madaline Espey Aarthi Narayanan Rebecca L. Heise Farhang Alem Daniel E. Conway SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells Scientific Reports |
| title | SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells |
| title_full | SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells |
| title_fullStr | SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells |
| title_full_unstemmed | SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells |
| title_short | SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells |
| title_sort | sars cov 2 s protein expression drives syncytia formation in endothelial cells |
| url | https://doi.org/10.1038/s41598-025-86242-1 |
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