Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission
Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/2/796 |
| _version_ | 1797493302063267840 |
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| author | Anett Hudák Gábor Veres Annamária Letoha László Szilák Tamás Letoha |
| author_facet | Anett Hudák Gábor Veres Annamária Letoha László Szilák Tamás Letoha |
| author_sort | Anett Hudák |
| collection | DOAJ |
| description | Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread. |
| first_indexed | 2024-03-10T01:18:04Z |
| format | Article |
| id | doaj.art-67da51e609024e618dbebd3d7b946559 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:18:04Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-67da51e609024e618dbebd3d7b9465592023-11-23T14:04:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-0123279610.3390/ijms23020796Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior TransmissionAnett Hudák0Gábor Veres1Annamária Letoha2László Szilák3Tamás Letoha4Pharmacoidea Ltd., 6726 Szeged, HungaryPharmacoidea Ltd., 6726 Szeged, HungaryAlbert Szent-Györgyi Clinical Center, Department of Medicine, Faculty of Medicine, University of Szeged, 6720 Szeged, HungaryPharmacoidea Ltd., 6726 Szeged, HungaryPharmacoidea Ltd., 6726 Szeged, HungaryEmerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread.https://www.mdpi.com/1422-0067/23/2/796SARS-CoV-2Delta variantviral transmissioncellular entrysyndecanheparan sulfate proteoglycans |
| spellingShingle | Anett Hudák Gábor Veres Annamária Letoha László Szilák Tamás Letoha Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission International Journal of Molecular Sciences SARS-CoV-2 Delta variant viral transmission cellular entry syndecan heparan sulfate proteoglycans |
| title | Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission |
| title_full | Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission |
| title_fullStr | Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission |
| title_full_unstemmed | Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission |
| title_short | Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission |
| title_sort | syndecan 4 is a key facilitator of the sars cov 2 delta variant s superior transmission |
| topic | SARS-CoV-2 Delta variant viral transmission cellular entry syndecan heparan sulfate proteoglycans |
| url | https://www.mdpi.com/1422-0067/23/2/796 |
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