ACE2 Can Act as the Secondary Receptor in the FcγR-Dependent ADE of SARS-CoV-2
38 Pages Posted: 23 Aug 2021 Publication Status: Published
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ACE2 Can Act as the Secondary Receptor in the FcγR-Dependent ADE of SARS-CoV-2
ACE2 Can Act as the Secondary Receptor in the FcγR-Dependent ADE of SARS-CoV-2
Abstract
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 XG005 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, and the maximum induction concentration of ADE was correlated with IC50, implying that part of unneutralized S protein is essential for ADE. The enhanced infectivity of 614G variant was higher than that of 614D wildtype in the presence of antibodies, further indicating that ADE may be influenced by the virus strains with different ACE2 binding affinity and infectivity. 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 identified a novel ADE mechanism for neutralizing antibodies against SARS-CoV-2. In certain circumstance, ACE2 may act as the secondary receptor in the antibody and FcγR-mediated enhanced entry of SARS-CoV-2.
Funding: This work is supported by National Key R&D Program of China (2020YFA0707600), Natural Science Foundation of China (82170015), Medical and Health Science Technology Innovation Project of Chinese Academy of Medical Sciences (2020-I2M-2-014), Project of BRC-BC (Biomedical Translational Engineering Research Center of BUCT-CJFH) (XK2020-09), Natural Science Foundation of China (82041011/H0104 & 81800002/H0101); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS 2018-I2M-1-003 & 2020-I2M-CoV19-005).
Declaration of Interests: The authors declare no competing interests.
Ethics Approval Statement: The plasma from convalescent patients were collected 6 months after their discharge, with informed consent signed by every patient. The procedures were approved by the Ethics Committee in China- Japan Friendship Hospital (Beijing, China), and complied with all relevant ethical regulations regarding human research.
Keywords: SARS CoV 2, antibody dependent enhancement, Fc γ receptors, c , ACE2
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