SARS-CoV-2 infection involves cell attachment and membrane fusion. However, the ACE2 receptor is paradoxically located at low levels in the respiratory system13. This suggests that other mechanisms may be available to facilitate infection. We show that C-type lectins DC-SIGN, DC-SIGN, and L-SIGN function as attachment receptors. They enhance ACE2-mediated infections and modulate the neutralizing activities of various spike-specific antibodies. While antibodies to the N-terminal and conserved sites at the base of Receptor Binding Domains (RBD) are not effective in neutralizing ACE2-over-expressing cells, they can block lectin-facilitated infections. While antibodies to the Receptor Binding Motif are potently neutralizing ACE2-expressing cells, they do not effectively neutralize infection in cells expressing DCSIGN or LSIGN. They also trigger fusogenic rearrangement and cell-to-cell fusion by activating the spike. These findings reveal a lectin-dependent pathway which enhances ACE2-dependent SARS-CoV-2 infection and distinct mechanisms for neutralization by different spike-specific antibodies.
