Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies.

Lempp, Florian A; Soriaga, Leah; Montiel-Ruiz, Martin; Benigni, Fabio; Noack, Julia; Park, Young-Jun; Bianchi, Siro; Walls, Alexandra C; Bowen, John E; Zhou, Jiayi; Kaiser, Hannah; Joshi, Anshu; Agostini, Maria; Meury, Marcel; Dellota, Exequiel; Jaconi, Stefano; Cameroni, Elisabetta; Martinez-Picado, Javier; Vergara-Alert, Júlia; Izquierdo-Useros, Nuria; Virgin, Herbert W; Lanzavecchia, Antonio; Veesler, David; Purcell, Lisa; Telenti, Amalio; Corti, Davide

SARS-CoV-2 infection, which involves both cell attachment and membrane fusion, relies on the ACE2 receptor that is paradoxically found at low levels in the respiratory tract1-3, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding Ig-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain (NTD) or to the conserved site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif (RBM), while potently neutralizing infection of ACE2 over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.