SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation

EMBO J. 2021 Dec 15;40(24):e108944. doi: 10.15252/embj.2021108944. Epub 2021 Oct 25.


Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS-CoV-2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighboring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha (B.1.1.7) and Beta (B.1.351) spread and fusion in cell cultures, compared with the ancestral D614G strain. Alpha and Beta replicated similarly to D614G strain in Vero, Caco-2, Calu-3, and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Variant spike proteins displayed higher ACE2 affinity compared with D614G. Alpha, Beta, and D614G fusion was similarly inhibited by interferon-induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes modified fusogenicity, binding to ACE2 or recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS-CoV-2 emerging variants display enhanced syncytia formation.

Keywords: SARS-CoV-2; coronavirus; fusion; spike; syncytia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Caco-2 Cells
  • Cell Line
  • Chlorocebus aethiops
  • Giant Cells / drug effects
  • Giant Cells / metabolism
  • Giant Cells / virology*
  • HEK293 Cells
  • Humans
  • Mutation*
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / physiology*
  • Spike Glycoprotein, Coronavirus / genetics*
  • Vero Cells
  • Virus Replication / drug effects


  • Antibodies, Monoclonal
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants