ACE2 can act as the secondary receptor in the FcγR-dependent ADE of SARS-CoV-2 infection

Zai Wang; Tingting Deng; Yulian Zhang; Wenquan Niu; Qiangqiang Nie; Shengnan Yang; Peipei Liu; Pengfei Pei; Long Chen; Haibo Li; Bin Cao

doi:10.1016/j.isci.2021.103720

ACE2 can act as the secondary receptor in the FcγR-dependent ADE of SARS-CoV-2 infection

iScience. 2022 Jan 21;25(1):103720. doi: 10.1016/j.isci.2021.103720. Epub 2021 Dec 31.

Authors

Zai Wang¹, Tingting Deng¹, Yulian Zhang^{2

3}, Wenquan Niu¹, Qiangqiang Nie⁴, Shengnan Yang^{5

6

7

8}, Peipei Liu^{5

6

9}, Pengfei Pei¹⁰, Long Chen¹⁰, Haibo Li^{5

6}, Bin Cao^{5

6

11

12}

Affiliations

¹ Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
² Department of Neurosurgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.
³ Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China.
⁴ Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China.
⁵ Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
⁶ National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
⁷ Harbin Medical University, Harbin, Heilongjiang, China.
⁸ Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, 261 Taierzhuang South Road, Tianjin, China.
⁹ Graduate School of Peking Union Medical College, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
¹⁰ Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
¹¹ Department of Respiratory Medicine, Capital Medical University, Beijing, China.
¹² Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, China.

Abstract

It is unknown whether antibody-mediated enhancement (ADE) contributes to the pathogenesis of COVID-19, and the conditions for ADE needs to be elucidated. We demonstrated that without inducing an ACE2-independent ADE on Raji cells, the neutralizing antibody CB6, a mouse anti-S1 serum and convalescent plasma, induced ADE on cells expressing FcγRIIA/CD32A and low levels of endogenous ACE2. ADE occurred at sub-neutralizing antibody concentrations, indicating that unneutralized S protein was required for ADE. The enhanced infectivity of 614G variant was higher than that of 614D wildtype in the presence of antibodies, further suggesting that ADE may be influenced by virus strains with different ACE2-binding affinity. Finally, knockdown of ACE2 or treatment with a fusion-inhibition peptide EK1C4 significantly reduced ADE. In conclusion, we identified an ADE mechanism mediated by neutralizing antibodies against SARS-CoV-2. ACE2 may act as a secondary receptor required for the antibody- and FcγR-mediated enhanced entry of SARS-CoV-2.

Keywords: Immunology; Virology.