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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates virus entry by binding to the host cell receptor, human angiotensin converting enzyme 2 (hACE2), and catalyzing virus?host membrane fusion. The S protein also mediates cell?cell fusion, potentially allowing the virus to spread virion-independently. Here, we compared the fusogenicity of SARS-CoV-2 variant S proteins using a cell?cell fusion assay. In cells overexpressing hACE2, cell?cell fusion ability of all tested SARS-CoV-2 variants was similar to that of the Wuhan-Hu-1 strain. However, in cells with endogenous hACE2, SARS-CoV-2 variants, especially the Delta variant, stimulated significantly greater cell?cell fusion than the original strain. Our results showed that the Delta variant S protein is highly fusogenic and can spread rapidly by utilizing small amounts of hACE2.
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