Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism that is distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature. [Display omitted] •Neutrophils in pediatric COVID-19 express an interferon-stimulated gene response•MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell signature•Neutrophil activation and extensive spontaneous NETosis are seen in MIS-C•SARS-CoV-2 spike immune complexes, especially IgA immune complexes, trigger NETs Boribong, LaSalle, et al. extensively profile gene expression, protein production, and functionality of neutrophils from children with acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C) to define neutrophil responses driving distinct SARS-CoV-2 disease states. They propose a model whereby neutrophil activation elicits endothelial dysfunction and cardiovascular complications within MIS-C.