Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant's Superior Transmission

Int J Mol Sci. 2022 Jan 12;23(2):796. doi: 10.3390/ijms23020796.


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.

Keywords: Delta variant; SARS-CoV-2; cellular entry; heparan sulfate proteoglycans; syndecan; viral transmission.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / antagonists & inhibitors
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • COVID-19 / transmission*
  • Cell Line
  • Heparan Sulfate Proteoglycans / antagonists & inhibitors
  • Heparan Sulfate Proteoglycans / metabolism
  • Humans
  • Protein Binding
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • SARS-CoV-2 / metabolism*
  • SARS-CoV-2 / pathogenicity*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Syndecan-4 / genetics
  • Syndecan-4 / metabolism*
  • Virus Internalization


  • Heparan Sulfate Proteoglycans
  • Recombinant Proteins
  • SDC4 protein, human
  • Spike Glycoprotein, Coronavirus
  • Syndecan-4
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants