The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells
Severe COVID-19 is characterized by angiogenic features, such as intussusceptive angiogenesis, endothelialitis, and activation of procoagulant pathways. This pathological state can be ascribed to a direct SARS-CoV-2 infection of human lung ECs. Recently, we showed the capability of SARS-CoV-2 to inf...
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MDPI AG
2023-01-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/2/332 |
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| author | Antonella Bugatti Federica Filippini Serena Messali Marta Giovanetti Cosetta Ravelli Alberto Zani Massimo Ciccozzi Arnaldo Caruso Francesca Caccuri |
| author_facet | Antonella Bugatti Federica Filippini Serena Messali Marta Giovanetti Cosetta Ravelli Alberto Zani Massimo Ciccozzi Arnaldo Caruso Francesca Caccuri |
| author_sort | Antonella Bugatti |
| collection | DOAJ |
| description | Severe COVID-19 is characterized by angiogenic features, such as intussusceptive angiogenesis, endothelialitis, and activation of procoagulant pathways. This pathological state can be ascribed to a direct SARS-CoV-2 infection of human lung ECs. Recently, we showed the capability of SARS-CoV-2 to infect ACE2-negative primary human lung microvascular endothelial cells (HL-mECs). This occurred through the interaction of an Arg-Gly-Asp (RGD) motif, endowed on the Spike protein at position 403–405, with α<sub>v</sub>β<sub>3</sub> integrin expressed on HL-mECs. HL-mEC infection promoted the remodeling of cells toward a pro-inflammatory and pro-angiogenic phenotype. The RGD motif is distinctive of SARS-CoV-2 Spike proteins up to the Omicron BA.1 subvariant. Suddenly, a dominant D405N mutation was expressed on the Spike of the most recently emerged Omicron BA.2, BA.4, and BA.5 subvariants. Here we demonstrate that the D405N mutation inhibits Omicron BA.5 infection of HL-mECs and their dysfunction because of the lack of Spike/integrins interaction. The key role of ECs in SARS-CoV-2 pathogenesis has been definitively proven. Evidence of mutations retrieving the capability of SARS-CoV-2 to infect HL-mECs highlights a new scenario for patients infected with the newly emerged SARS-CoV-2 Omicron subvariants, suggesting that they may display less severe disease manifestations than those observed with previous variants. |
| first_indexed | 2024-03-11T08:00:42Z |
| format | Article |
| id | doaj.art-6539e47d90ca434c9315c37fbf8caa3b |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T08:00:42Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-6539e47d90ca434c9315c37fbf8caa3b2023-11-16T23:47:34ZengMDPI AGViruses1999-49152023-01-0115233210.3390/v15020332The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial CellsAntonella Bugatti0Federica Filippini1Serena Messali2Marta Giovanetti3Cosetta Ravelli4Alberto Zani5Massimo Ciccozzi6Arnaldo Caruso7Francesca Caccuri8Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyLaboratório de Flavivirus, Instituto Oswaldo Cruz, Rio de Janeiro 21040-900, BrazilSection of General Pathology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalyUnit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, 00128 Rome, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, ItalySevere COVID-19 is characterized by angiogenic features, such as intussusceptive angiogenesis, endothelialitis, and activation of procoagulant pathways. This pathological state can be ascribed to a direct SARS-CoV-2 infection of human lung ECs. Recently, we showed the capability of SARS-CoV-2 to infect ACE2-negative primary human lung microvascular endothelial cells (HL-mECs). This occurred through the interaction of an Arg-Gly-Asp (RGD) motif, endowed on the Spike protein at position 403–405, with α<sub>v</sub>β<sub>3</sub> integrin expressed on HL-mECs. HL-mEC infection promoted the remodeling of cells toward a pro-inflammatory and pro-angiogenic phenotype. The RGD motif is distinctive of SARS-CoV-2 Spike proteins up to the Omicron BA.1 subvariant. Suddenly, a dominant D405N mutation was expressed on the Spike of the most recently emerged Omicron BA.2, BA.4, and BA.5 subvariants. Here we demonstrate that the D405N mutation inhibits Omicron BA.5 infection of HL-mECs and their dysfunction because of the lack of Spike/integrins interaction. The key role of ECs in SARS-CoV-2 pathogenesis has been definitively proven. Evidence of mutations retrieving the capability of SARS-CoV-2 to infect HL-mECs highlights a new scenario for patients infected with the newly emerged SARS-CoV-2 Omicron subvariants, suggesting that they may display less severe disease manifestations than those observed with previous variants.https://www.mdpi.com/1999-4915/15/2/332SARS-CoV-2Omicron variantendothelial cell dysfunctionintegrins |
| spellingShingle | Antonella Bugatti Federica Filippini Serena Messali Marta Giovanetti Cosetta Ravelli Alberto Zani Massimo Ciccozzi Arnaldo Caruso Francesca Caccuri The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells Viruses SARS-CoV-2 Omicron variant endothelial cell dysfunction integrins |
| title | The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells |
| title_full | The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells |
| title_fullStr | The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells |
| title_full_unstemmed | The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells |
| title_short | The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells |
| title_sort | d405n mutation in the spike protein of sars cov 2 omicron ba 5 inhibits spike integrins interaction and viral infection of human lung microvascular endothelial cells |
| topic | SARS-CoV-2 Omicron variant endothelial cell dysfunction integrins |
| url | https://www.mdpi.com/1999-4915/15/2/332 |
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