Induction of Cell-Cell Fusion

Many enveloped viruses induce multinucleated cells (syncytia) in later stages of viral infection. The membrane fusion that drives these cell-cell fusion events are caused by the same machinery that underlies viral entry. The presence of infected syncytial pneumocytes in severe COVID-19 patients is well established. However, it is currently unclear if syncytia formation is also a feature of milder or asymptomatic SARS-CoV-2 infections. These syncytia are also thought to facilitate replication and evasion of the host immune response (for a recent review on Spike-mediated fusion and syncytia formation see Rajah et al, 2022). Experiments that utilize co-cultures of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike protein, result in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. Studies on SARS-CoV-2 identified similar syncytia. Formation of the ACE2/spike protein complex drives fusion events that proceed from finger-like projections, forming synapses between cells to development of a fusion pore and subsequent membrane fusion (reviewed in Rajah et al, 2022; Rey, 2021). Notably cleaving the spike protein into S1 and S2 sub-fragments appears to increase the probability of S1/ACE2 fusion.

Summary from Reactome (R-HSA-9733458), read 2026-09-23.