(A) A375 cells were transduced with indicated activating sgRNAs and incubated with SARS-CoV-2 spike S1-Fc fusion protein. Protein binding was measured by flow cytometry with MFI shown. (B) HeLa cells were transduced with indicated activating sgRNAs and incubated with SARS-CoV-2 spike S1-Fc fusion protein. Protein binding was measured by flow cytometry with MFI shown. (C) Dose-dependent binding of SARS-CoV-2 spike protein (Wuhan-Hu-1) to both ACE2 and LRRC15 with an Fc tag was determined by ELISA. Human IgG1 was included as a negative control. Dots indicate means of duplicates. (D) HeLa cells were transduced with indicated activating sgRNAs and incubated with SARS-CoV-2 spike NTD-Fc or RBD-Fc fusion protein. Protein binding was measured by flow cytometry with MFI shown. (E) The binding of the SARS-CoV-2 RBD and NTD to LRRC15 was measured by ELISA. For underlying data, see S3 Data. ACE2, angiotensin-converting enzyme 2; LRRC15, leucin-rich repeat-containing 15; MFI, mean fluorescence intensity; NTD, N-terminal domain; RBD, receptor-binding domain; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; sgRNA, single guide RNA.