Induction of Cell-Cell Fusion

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 (Zhang et al., 2021). 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 (Sanders et al., 2021). Studies on SARS-CoV-2 identified similar syncytia (Buchrieser et al., 2020; Hoffmann et al., 2020a; Ou et al., 2020; Xia et al., 2020). 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 (Hoffmann et al., 2020a).
The Alpha, Beta, and Delta variants of SARS-CoV-2 display enhanced syncytia formation (Cheng et al, 2021; Rajah et al, 2021). An additional phenomenon with SARS-CoV-2 syncytia is their targeting of lymphocytes for internalization and cell-in-cell mediated elimination, potentially contributing to lymphopenia and pathogenesis in COVID-19 patients (Zhang et al, 2021).