CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for\nSARS-CoV‑2
Razie Amraei, Wenqing Yin, Marc A. Napoleon, Ellen L. Suder, Jacob Berrigan, Qing Zhao, Judith Olejnik, Kevin Brown Chandler, Chaoshuang Xia, Jared Feldman, Blake M. Hauser, Timothy M. Caradonna, Aaron G. Schmidt, Suryaram Gummuluru, Elke Mühlberger, Vipul C. Chitalia, Catherine E. Costello, Nader Rahimi
Abstract
As the COVID-19 pandemic\ncontinues to spread, investigating the\nprocesses underlying the interactions between SARS-CoV-2 and its hosts\nis of high importance. Here, we report the identification of CD209L/L-SIGN\nand the related protein CD209/DC-SIGN as receptors capable of mediating\nSARS-CoV-2 entry into human cells. Immunofluorescence staining of\nhuman tissues revealed prominent expression of CD209L in the lung\nand kidney epithelia and endothelia. Multiple biochemical assays using\na purified recombinant SARS-CoV-2 spike receptor-binding domain (S-RBD)\nor S1 encompassing both N termal domain and RBD and ectopically expressed\nCD209L and CD209 revealed that CD209L and CD209 interact with S-RBD.\nCD209L contains two <i>N</i>-glycosylation sequons, at sites\nN92 and N361, but we determined that only site N92 is occupied. Removal\nof the <i>N</i>-glycosylation at this site enhances the\nbinding of S-RBD with CD209L. CD209L also interacts with ACE2, suggesting\na role for heterodimerization of CD209L and ACE2 in SARS-CoV-2 entry\nand infection in cell types where both are present. Furthermore, we\ndemonstrate that human endothelial cells are permissive to SARS-CoV-2\ninfection, and interference with CD209L activity by a knockdown strategy\nor with soluble CD209L inhibits virus entry. Our observations demonstrate\nthat CD209L and CD209 serve as alternative receptors for SARS-CoV-2\nin disease-relevant cell types, including the vascular system. This\nproperty is particularly important in tissues where ACE2 has low expression\nor is absent and may have implications for antiviral drug development.