Mechanisms of Cell–Cell Fusion in SARS-CoV-2: An Evolving Strategy for Transmission and Immune Evasion

Early studies on the evolution of SARS-CoV-2 revealed mutations that favored host transmission of the virus and more efficient viral entry. However, cell-free virus spread is vulnerable to host-neutralizing antibodies. As population immunity developed, mutations that confer escape from neutralization were selected. Notably, cell syncytia formation wherein an infected cell fuses with a noninfected cell is a more efficient route of transmission that bypasses humoral immunity. Cell syncytia formation has been implicated in the pathogenicity of SARS-CoV-2 infection whilst compromising host transmission due to impaired whole virion release. Therefore, understanding the mechanisms of virus-mediated cell-cell fusion will aid in identifying and targeting more pathogenic strains of SARS-CoV-2. Whilst the general kinetics of cell-cell fusion have been known for decades, the specific mechanisms by which SARS-CoV-2 induces fusion are beginning to be elucidated. This is partially due to emergence of more reliable, high throughput methods of quantifying and comparing fusion efficiency in experimental models. Moreover, the ongoing inflammatory response and emerging health burden of long COVID may point to cell-cell fusion in the pathogenesis. In this review, we synthesize current understanding of SARS-CoV-2-mediated cell-cell fusion and its consequences on immune escape, viral persistence, and the innate immune response.