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

Brittany P Boribong; Thomas J LaSalle; Yannic C Bartsch; Felix Ellett; Maggie E Loiselle; Jameson P Davis; Anna L K Gonye; David B Sykes; Soroush Hajizadeh; Johannes Kreuzer; Shiv Pillai; Wilhelm Haas; Andrea G Edlow; Alessio Fasano; Galit Alter; Daniel Irimia; Moshe Sade-Feldman; Lael M Yonker

doi:10.1016/j.xcrm.2022.100848

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

Cell Rep Med. 2022 Dec 20;3(12):100848. doi: 10.1016/j.xcrm.2022.100848. Epub 2022 Nov 21.

Authors

Brittany P Boribong¹, Thomas J LaSalle², Yannic C Bartsch³, Felix Ellett⁴, Maggie E Loiselle⁵, Jameson P Davis⁵, Anna L K Gonye⁶, David B Sykes⁷, Soroush Hajizadeh⁸, Johannes Kreuzer⁹, Shiv Pillai³, Wilhelm Haas⁹, Andrea G Edlow¹⁰, Alessio Fasano¹, Galit Alter³, Daniel Irimia⁴, Moshe Sade-Feldman¹¹, Lael M Yonker¹²

Affiliations

¹ Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
² Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Health Sciences and Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA.
³ Harvard Medical School, Boston, MA 02115, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁴ Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁵ Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
⁸ Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹ Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Harvard Medical School, Boston, MA 02115, USA; Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Boston, MA 02114, USA; Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: msade-feldman@mgh.harvard.edu.
¹² Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: lyonker@mgh.harvard.edu.

Abstract

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.

Keywords: COVID-19; RNA sequencing; multisystem inflammatory syndrome in children; neutrophil; neutrophil extracellular traps; pediatrics.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

COVID-19*
Child
Humans
Neutrophils*
SARS-CoV-2
Systemic Inflammatory Response Syndrome / diagnosis

Supplementary concepts

pediatric multisystem inflammatory disease, COVID-19 related

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding