Antibody-mediated spike activation promotes cell-cell transmission of SARS-CoV-2

Abstract

The COVID pandemic fueled by emerging SARS-CoV-2 new variants of concern remains a major global health concern, and the constantly emerging mutations present challenges to current therapeutics. The spike glycoprotein is not only essential for the initial viral entry, but is also responsible for the transmission of SARS-CoV-2 components via syncytia formation. Spike-mediated cell-cell transmission is strongly resistant to extracellular therapeutic and convalescent antibodies via an unknown mechanism. Here, we describe the antibody-mediated spike activation and syncytia formation on cells displaying the viral spike. We found that soluble antibodies against receptor binding motif (RBM) are capable of inducing the proteolytic processing of spike at both the S1/S2 and S2’ cleavage sites, hence triggering ACE2-independent cell-cell fusion. Mechanistically, antibody-induced cell-cell fusion requires the shedding of S1 and exposure of the fusion peptide at the cell surface. By inhibiting S1/S2 proteolysis, we demonstrated that cell-cell fusion mediated by spike can be re-sensitized towards antibody neutralization in vitro. Lastly, we showed that cytopathic effect mediated by authentic SARS-CoV-2 infection remain unaffected by the addition of extracellular neutralization antibodies. Hence, these results unveil a novel mode of antibody evasion and provide insights for antibody selection and drug design strategies targeting the SARS-CoV-2 infected cells.

Interleukin-1 prevents SARS-CoV-2-induced membrane fusion to restrict viral transmission via induction of actin bundles

“…SARS-CoV-2 infection induces cell-cell fusion (also known as syncytia formation) in multiple cell types including lung epithelial cells, neurons and glia (Martínez-Mármol et al, 2023). Syncytia of SARS-CoV-2 infected cells with neighboring cells could potentially contribute to increased viral transmission and pathogenicity in the infected host (Rajah, Bernier, Buchrieser, & Schwartz, 2022), which also makes the virus insensitive to extracellular neutralizing antibodies (Li et al, 2022; Yu et al, 2023). Moreover, syncytia formation among pneumocytes with long-term persistence of viral RNA has been observed in the lung autopsy of deceased COVID-19 donors, which may contribute to prolonged clearance of the virus and long COVID symptoms (Bussani et al, 2020).…”