A COVID-19 antibody curbs SARS-CoV-2 nucleocapsid protein-induced complement hyper-activation

Kang, Sisi; Yang, Mei; He, Suhua; Wang, Yueming; Chen, Xiaoxue; Chen, Yao-Qing; Hong, Zhongsi; Liu, Jing; Jiang, Guanmin; Chen, Qiuyue; Zhou, Ziliang; Zhou, Zhechong; Huang, Zhaoxia; Huang, Xi; He, Huanhuan; Zheng, Weihong; Liao, Hua-Xin; Xiao, Fei; Shan, Hong; Chen, Shoudeng

Although human antibodies elicited by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-directed antibodies. Herein, we isolated and profiled a panel of 32 N protein-specific monoclonal antibodies (mAb) from a quick recovery coronavirus disease-19 (COVID-19) convalescent, who had dominant antibody responses to SARS-CoV-2 N protein rather than to Spike protein. The complex structure of N protein RNA binding domain with the highest binding affinity mAb nCoV396 reveals the epitopes and antigen’s allosteric changes. Functionally, a virus-free complement hyper-activation analysis demonstrates that nCoV396 specifically compromises N protein-induced complement hyper-activation, a risk factor for morbidity and mortality in COVID-19, thus paving the way for functional anti-N mAbs identification. One Sentence Summary B cell profiling, structural determination, and protease activity assays identify a functional antibody to N protein.