Wye‐Lup Kong, Yi-Hsuan Chang, Wei-Nan Chen, Wei-Nan Chen, Yi-Fu Wang, Dong-Yen Tsai, Wenyu Chen, Wenyu Chen, Fang-Ju Chang, I‐Ying Lin, Ming-Tsan Liu, Wan-Chen Hsieh, Yi‐Hua Chen, Yi-Shiuan Tzeng, Szu-Teng Ma, Kai Xuan Tin, Chih-Heng Huang, Chun‐Che Liao, Jian-Jong Liang, Yu‐Chi Chou, Yen-Chen Chen, Jia-Tsrong Jan, Yen-Chen Chen, Deepa Sridharan, Takashi Angata, Yi‐Ling Lin, Shih‐Yu Chen, Mei‐Yeh Jade Lu, Kuo‐I Lin
Beyond direct neutralization, antibodies clear SARS-CoV-2 by triggering antibody-dependent cellular cytotoxicity (ADCC), which guides natural killer (NK) cells to eliminate infected cells. To understand ADCC’s role in COVID-19, we analyze samples from primary patients and find that plasma ADCC activity correlated with a slower rate of viral clearance. To explore this mechanism, we isolate a monoclonal antibody with potent ADCC activity against SARS-CoV-2 variants. In infected mice, this antibody activates an antiviral transcriptional program in the lungs that suppresses viral RNA synthesis. Spatial transcriptomic analysis of mice treated with ADCC-mediating antibodies reveals that low expression of cytolytic NK cell markers and NK cell cluster-associated gene pathways are linked to pulmonary viral clearance. Furthermore, human peripheral NK cells activate pre-existing NK cell clusters when engaging the ADCC antibody. Our findings demonstrate that ADCC-mediating antibodies recruit NK subsets with low baseline cytolytic signatures to facilitate effective viral clearance. Spatial transcriptomics and CyTOF reveal that an isolated monoclonal ADCC antibody promotes SARS-CoV-2 clearance by recruiting specific NK subsets with low baseline cytolytic signatures and activated cluster-associated pathways.