CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells

The spike protein (S) of SARS-CoV-2 mediates entry into human cells by interacting with human angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Here, we report identification of CD209L/L-SIGN and a related protein, CD209/DSIGN as alternative receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed a prominent expression of CD209L in the lung and kidney epithelial and endothelial cells of small and medium-sized vessels, whereas CD209 was detected only in a limited number of cell types. Biochemical assays revealed that ectopically expressed CD209L and CD209 bind to S-RBD and mediate SARS-CoV-2 S-pseudotyped virus entry. Furthermore, we demonstrate that human endothelial cells endogenously express CD209L and are permissive to SARS-CoV-2 infection. Soluble CD209L-Fc neutralized virus entry. Our observations show that CD209L and CD209 serve as alternative receptors for SARS-CoV-2 in disease-relevant cell types, including the vascular system. This may have implications for antiviral drug development.