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.
【저자키워드】 SARS-CoV-2, delta variant, Viral transmission, heparan sulfate proteoglycans, cellular entry, syndecan, 【초록키워드】 COVID-19, ACE2, vaccination, Mutation, threat, spike glycoprotein, SARS-CoV-2 variant, Infection, Delta, lung, Transmission, in vitro, heparin, molecular mechanism, delta variant, virus, Spike protein, heparan sulfate, Spread, Protein, B.1.617, Lineage, syndecan, molecular, expression, interactions, cellular, cellular uptake, pseudoviruses, sulfate, Threats, attachment, domain, complexity, molecular mechanisms, wild-type, knockdown, molecular interaction, positive, Modification, Specific, higher affinity, being, SARS-CoV-2 pseudoviruses, syndecan-4, block, isoform, ENhance, addition, added, mutated, reduce, electrostatic, Proteoglycan, exogenously, driver, the SARS-CoV-2, 【제목키워드】 Delta, facilitator, Superior, the SARS-CoV-2,