Key Points
- The receptor binding domain (RBD) of SARS-CoV-2 bears sequence and overall ABO blood binding similarity with human galectins.
- SARS-CoV-2 preferentially infects blood group A cells, providing a direct link between blood group A expression and increased infection.
Among risk factors for SARS-CoV-2, ABO(H) blood group antigens have been one of the most recognized predictors of infection. However, the mechanisms whereby ABO(H) antigens influence susceptibility to COVID-19 remain incompletely understood. The receptor binding domain (RBD) of SARS-CoV-2, which facilitates host cell engagement, bears significant similarity to galectins, an ancient family of carbohydrate binding proteins. As ABO(H) blood group antigens are carbohydrates, we compared the glycan binding specificity of the SARS-COV-2 RBD with galectins. Similar to the binding profile of several galectins, the RBDs of SARS-CoV-2, including Delta and Omicron variants, exhibited specificity for blood group A. Not only did each RBD recognize blood group A in a glycan array format, but each SARS-CoV-2 virus likewise displayed a preferential ability to infect blood group A expressing cells. Preincubation of blood group A cells with a blood group binding galectin specifically inhibited the blood group A enhancement of SARS-CoV-2 infection, while similar incubation with a galectin that does not recognize blood group antigens failed to impact SARS-CoV-2 infection. These results demonstrate that SARS-CoV-2 can engage blood group A, providing a direct link between ABO(H) blood group expression and SARS-CoV-2 infection.