ACE2 Can Act as the Secondary Receptor in the FcγR-Dependent ADE of SARS-CoV-2

Currently, it is not clear whether antibody-mediated enhancement (ADE) is involved in the pathogenesis of COVID-19, and the occurrence condition for ADE needs to be elucidated. We demonstrated that different from the reported RBD-targeting neutralizing antibody GX005 which elicits an ACE2-independent ADE on Raji cells, neutralizing antibody CB6, mouse anti-S1 serum and convalescent plasma could not elicit ADE on Raji cells; instead, they could elicit ADE on cells with FcγRIIA/CD32A expression and small amount of endogenous ACE2. ADE occurred at sub-neutralizing antibody concentrations, implying that part of unneutralized S protein is essential for ADE. ADE was proved to be FcγRII-dependent, and knockdown of ACE2 or the application of fusion-inhibition peptide EK1C4 significantly impaired ADE. In conclusion, our results demonstrated that ACE2 may act as the secondary receptor in the antibody and FcγR-mediated enhanced entry of SARS-CoV-2.