Unraveling the immune landscape and molecular signatures of antibody-dependent cellular cytotoxicity in SARS-CoV-2 clearance

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.