Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children
Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children
Abstract Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory systemic illness characterized by SARS-CoV-2 antigenemia, cytokine storm and immune dysregulation; however, the role of the neutrophil has yet to be defined. In adults with severe COVID-19, neutrophil activation has been shown to be central to overactive inflammatory responses and complications. Thus, we sought to define neutrophil activation in children with MIS-C and acute COVID-19. We collected samples from 141 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 67 pediatric controls. We found that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, which is markedly different than the neutrophil interferon-stimulated gene (ISG) response observed in pediatric patients during acute SARS-CoV-2 infection. Moreover, we identified signatures of neutrophil activation and degranulation with high levels of spontaneous neutrophil extracellular trap (NET) formation in neutrophils isolated from fresh whole blood of MIS-C patients. Mechanistically, we determined that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Overall, our findings suggest that the hyperinflammatory presentation of MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia through uncontrolled neutrophil activation and NET release in the vasculature. One Sentence SummaryCirculating SARS-CoV-2 antigen:antibody immune complexes in Multisystem Inflammatory Syndrome in Children (MIS-C) drive hyperinflammatory and coagulopathic neutrophil extracellular trap (NET) formation and neutrophil activation pathways, providing insight into disease pathology and establishing a divergence from neutrophil signaling seen in acute pediatric COVID-19.
Boribong Brittany P.、Davis Jameson P.、Gonye Anna L. K.、Pillai Shiv、Irimia Daniel、Sade-Feldman Moshe、Hajizadeh Soroush、LaSalle Thomas J.、Alter Galit、Kreuzer Johannes、Yonker Lael M.、Edlow Andrea、Loiselle Maggie E.、Bartsch Yannic C.、Haas Wilhelm、Fasano Alessio、Ellett Felix
Mucosal Immunology and Biology Research Center, Massachusetts General Hospital||Department of Pediatrics, Massachusetts General Hospital||Department of Medicine, Harvard Medical SchoolMucosal Immunology and Biology Research Center, Massachusetts General HospitalCenter for Cancer Research, Department of Medicine, Massachusetts General Hospital||Broad Institute of MIT and HarvardDepartment of Medicine, Harvard Medical School||Ragon Institute of MGH, MIT and HarvardBioMEMS Resource Center, Department of Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical SchoolDepartment of Medicine, Harvard Medical School||Center for Cancer Research, Department of Medicine, Massachusetts General Hospital||Broad Institute of MIT and HarvardDepartment of Medicine, Harvard Medical School||Center for Cancer Research, Department of Medicine, Massachusetts General Hospital||Broad Institute of MIT and HarvardCenter for Cancer Research, Department of Medicine, Massachusetts General Hospital||Broad Institute of MIT and HarvardDepartment of Medicine, Harvard Medical School||Ragon Institute of MGH, MIT and HarvardDepartment of Medicine, Harvard Medical School||Center for Cancer Research, Department of Medicine, Massachusetts General HospitalMucosal Immunology and Biology Research Center, Massachusetts General Hospital||Department of Pediatrics, Massachusetts General Hospital||Department of Medicine, Harvard Medical SchoolDepartment of Medicine, Harvard Medical School||Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine||Vincent Center for Reproductive Biology, Massachusetts General HospitalMucosal Immunology and Biology Research Center, Massachusetts General HospitalDepartment of Medicine, Harvard Medical School||Ragon Institute of MGH, MIT and HarvardDepartment of Medicine, Harvard Medical School||Center for Cancer Research, Department of Medicine, Massachusetts General HospitalMucosal Immunology and Biology Research Center, Massachusetts General Hospital||Department of Pediatrics, Massachusetts General Hospital||Department of Medicine, Harvard Medical School||European Biomedical Research Institute of Salerno (EBRIS)BioMEMS Resource Center, Department of Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School
儿科学基础医学临床医学
Boribong Brittany P.,Davis Jameson P.,Gonye Anna L. K.,Pillai Shiv,Irimia Daniel,Sade-Feldman Moshe,Hajizadeh Soroush,LaSalle Thomas J.,Alter Galit,Kreuzer Johannes,Yonker Lael M.,Edlow Andrea,Loiselle Maggie E.,Bartsch Yannic C.,Haas Wilhelm,Fasano Alessio,Ellett Felix.Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children[EB/OL].(2025-03-28)[2025-05-16].https://www.biorxiv.org/content/10.1101/2021.12.18.473308.点此复制
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