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

doi:10.1016/j.xcrm.2022.100848

. 2022 Dec 20;3(12):100848.

doi: 10.1016/j.xcrm.2022.100848. Epub 2022 Nov 21.

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

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.

PMID: 36476388
PMCID: PMC9676175
DOI: 10.1016/j.xcrm.2022.100848

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

Brittany P Boribong et al. Cell Rep Med. 2022.

. 2022 Dec 20;3(12):100848.

doi: 10.1016/j.xcrm.2022.100848. Epub 2022 Nov 21.

Authors

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.

PMID: 36476388
PMCID: PMC9676175
DOI: 10.1016/j.xcrm.2022.100848

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.

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Conflict of interest statement

Declaration of interests M.S.-F. receives funding from Bristol-Myers Squibb. G.A. is a founder of Seromyx Systems, Inc. A.F. is co-founder of and stockholder in Alba Therapeutics.

Figures

**Figure 1**
Overview of cohort and experimental schematic Whole blood samples were collected from three cohorts: (1) pediatric healthy controls, (2) pediatric acute COVID-19 infection, and (3) multisystem inflammatory syndrome in children (MIS-C). Plasma collected from whole-blood samples was used in proteomic assays to quantify levels of protein and cell-free DNA. Isolated neutrophils were used in bulk RNA sequencing and NETosis assays. Patient samples were used in individual or multiple assays. See also Figure S1 and Tables S1 and S2.

**Figure 2**
Acute pediatric COVID-19 neutrophils are marked by a robust interferon-stimulated gene signature (A) Volcano plot showing differentially expressed genes between pediatric acute COVID-19 and healthy control samples. Color-coded points indicate genes that pass false discovery rate (FDR) correction with q < 0.05. (B) Gene set enrichment analysis for the differentially expressed genes in (A). Bar lengths correspond to normalized enrichment score (NES), with positive NES values indicating enrichment in COVID-19 and negative values indicating enrichment in healthy pediatric controls. Asterisks denote significance as defined in the figure. (C) UMAP of neutrophil bulk RNA sequencing (RNA-seq) samples from adults with acute COVID-19 and healthy controls from LaSalle et al. UMAP is color coded by cluster designation. Bottom, schematic illustrating several top genes associated with each neutrophil subtype. Neu-Lo, samples excluded from clustering based on estimated low neutrophil fraction by CIBERSORTx. (D) (Top) UMAP plots of neutrophil bulk RNA-seq data. Each point is one bulk sample, and points are color coded according to disease status. (Bottom) UMAPs of all neutrophil samples that were sequenced with bulk RNA-seq. Samples are colored according to their expression score of each neutrophil state metagene. (E) GSEA enrichment plots for the NMF1 (Pro-Neu), NMF3 (PD-L1+ ISG+), NMF5 (G-MDSC), and NMF6 (ISG+) signatures, the four NMF neutrophil signatures that passed FDR correction. Each point represents one gene in the gene signature. Positive scores denote enrichment in acute pediatric COVID-19, and negative scores denote enrichment in healthy controls. See also Tables S3, S4, and S5.

**Figure 3**
Neutrophils from patients with MIS-C display a strong G-MDSC signature and are characterized by altered metabolism (A) Volcano plot showing differentially expressed genes between MIS-C and pediatric healthy control samples. Color-coded points indicate genes that pass FDR correction with q < 0.05. (B) Gene set enrichment analysis for the differentially expressed genes in (A). Bar lengths correspond to NES, with positive NES values indicating enrichment in MIS-C and negative values indicating enrichment in healthy controls. Asterisks denote significance as defined in the figure. (C) GSEA enrichment plots for the NMF4 (Immature) and NMF5 (G-MDSC) signatures, the two NMF neutrophil signatures that passed FDR correction. (D) Heatmap displaying scaled RNA-seq expression values for gene markers distinguishing pediatric acute COVID-19 and MIS-C. The color coding on the right of the heatmap indicates whether the gene was differentially expressed in MIS-C versus COVID-19 and healthy or COVID-19 versus MIS-C or healthy. Color-coded bars above indicate disease status, cardiac involvement for patients with MIS-C, course of treatment, and days since the administration of steroids. See also Figures S2 and S3 and Tables S3, S4, and S5.

**Figure 4**
Fluorescence microscopy, cell-free DNA, and plasma protein markers implicate high levels of NETosis in MIS-C disease pathology (A) Neutrophils were isolated from patients with MIS-C or healthy controls and plated on a 96-well plate without any stimulus to measure neutrophil activation via spontaneous NET release. Scale bar: 50 μM. (B) Temporal dynamics of NET release in unstimulated neutrophils from healthy children (n = 7) and children with MIS-C (n = 7), as well as healthy neutrophils stimulated with 100 nM PMA (n = 7). (C) End-point percentage of NETosis in unstimulated neutrophils from healthy children and children with MIS-C and healthy neutrophils stimulated with 100 nM PMA. (D) Quantification of circulating cell-free DNA in plasma of healthy patients (n = 10), children with COVID-19 (n = 19), children with convalescent COVID-19 (n = 11), and children with MIS-C (n = 19). Displayed as fold increase from baseline (healthy controls). (E–H) Peak values of myeloperoxidase (E), lactoferrin (F), cathelicidin antimicrobial peptide (G), and collagenase matrix metallopeptidase 9 (H) quantified in plasma from pediatric controls (n = 23), children with acute COVID-19 (n = 19), and children with MIS-C (n = 13). (B) Mean values and SD are presented. (C) One-way ANOVA with multiple comparisons. Mean values and SD are presented. (D)–(H) Median values are shown with interquartile ranges; significance was determined by Kruskal-Wallis. Statistical significance is defined as ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001. See also Video S1.

**Figure 5**
SARS-CoV-2 spike immune complexes trigger NETosis (A) Plasma was collected from several children with non-COVID-19 illness, convalescent COVID-19, and MIS-C and pooled together. Pooled plasma was diluted at 1:10 and incubated with beads coated with spike proteins to generate immune complexes or without the presence of spike protein to measure the stimulation of plasma alone. Neutrophils were isolated from healthy children, stimulated, and visualized within four viewing channels of a microfluidic device. (B) Temporal dynamics of NET release in neutrophils (n = 8) stimulated with PBS, PBS-treated spike beads, non-COVID-19 plasma, non-COVID-19-plasma-coated spike beads, convalescent COVID-19 plasma, convalescent COVID-19-plasma-coated spike beads, MIS-C plasma, and MIS-C-plasma-coated spike beads. (C) End-point percentage of NET release in neutrophils (n = 8) stimulated with conditions described in (B). (D) Temporal dynamics of NET release in neutrophils (n = 8) stimulated with non-depleted MIS-C plasma, IgG-depleted MIS-C plasma, IgA-depleted MIS-C plasma, and MIS-C plasma depleted of both IgG and IgA. (E) End-point percentage of NET release in neutrophils (n = 8) stimulated with plasma as described in (D). (B-E) Mean values and SD are presented. (C and D) Significance was determined by one-way ANOVA with multiple comparisons. Statistical significance is defined as ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.0001. See also Figures S4 and S5 and Videos S2 and S3.

**Figure 6**
Schematic of the role of neutrophils in pediatric COVID-19 and MIS-C Acute SARS-CoV-2 infection begins in the respiratory epithelium, and interferon signaling induces ISG+ neutrophils in circulation. Weeks later, viral persistence in the gut lumen results in zonulin release from gut epithelial cells, leading to loss of tight junctions and SARS-CoV-2 antigen leakage. Finally, immune complexes trigger NETosis and induce G-MDSCs, resulting in endothelial dysfunction and cardiovascular complications.

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Update of

Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children.
Boribong BP, LaSalle TJ, Bartsch YC, Ellett F, Loiselle ME, Davis JP, Gonye ALK, Hajizadeh S, Kreuzer J, Pillai S, Haas W, Edlow A, Fasano A, Alter G, Irimia D, Sade-Feldman M, Yonker LM. Boribong BP, et al. bioRxiv [Preprint]. 2021 Dec 20:2021.12.18.473308. doi: 10.1101/2021.12.18.473308. bioRxiv. 2021. Update in: Cell Rep Med. 2022 Dec 20;3(12):100848. doi: 10.1016/j.xcrm.2022.100848 PMID: 34981052 Free PMC article. Updated. Preprint.

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References

1. LaSalle T.J., Gonye A.L.K., Freeman S.S., Kaplonek P., Gushterova I., Kays K.R., Manakongtreecheep K., Tantivit J., Rojas-Lopez M., Russo B.C., et al. Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients. Cell Rep. Med. 2022;3 doi: 10.1016/j.xcrm.2022.100779. - DOI - PMC - PubMed
1. Aschenbrenner A.C., Mouktaroudi M., Krämer B., Oestreich M., Antonakos N., Nuesch-Germano M., Gkizeli K., Bonaguro L., Reusch N., Baßler K., et al. Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. Genome Med. 2021;13:7. doi: 10.1186/s13073-020-00823-5. - DOI - PMC - PubMed
1. Meizlish M.L., Pine A.B., Bishai J.D., Goshua G., Nadelmann E.R., Simonov M., Chang C.H., Zhang H., Shallow M., Bahel P., et al. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv. 2021;5:1164–1177. doi: 10.1182/bloodadvances.2020003568. - DOI - PMC - PubMed
1. Schulte-Schrepping J., Reusch N., Paclik D., Baßler K., Schlickeiser S., Zhang B., Krämer B., Krammer T., Brumhard S., Bonaguro L., et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182:1419–1440.e23. doi: 10.1016/j.cell.2020.08.001. e1423. - DOI - PMC - PubMed
1. CDC . 2021. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C)https://www.cdc.gov/mis/mis-c/hcp/index.html

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[1] LaSalle T.J., Gonye A.L.K., Freeman S.S., Kaplonek P., Gushterova I., Kays K.R., Manakongtreecheep K., Tantivit J., Rojas-Lopez M., Russo B.C., et al. Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients. Cell Rep. Med. 2022;3 doi: 10.1016/j.xcrm.2022.100779. - DOI - PMC - PubMed

[2] LaSalle T.J., Gonye A.L.K., Freeman S.S., Kaplonek P., Gushterova I., Kays K.R., Manakongtreecheep K., Tantivit J., Rojas-Lopez M., Russo B.C., et al. Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients. Cell Rep. Med. 2022;3 doi: 10.1016/j.xcrm.2022.100779. - DOI - PMC - PubMed

[3] Aschenbrenner A.C., Mouktaroudi M., Krämer B., Oestreich M., Antonakos N., Nuesch-Germano M., Gkizeli K., Bonaguro L., Reusch N., Baßler K., et al. Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. Genome Med. 2021;13:7. doi: 10.1186/s13073-020-00823-5. - DOI - PMC - PubMed

[4] Aschenbrenner A.C., Mouktaroudi M., Krämer B., Oestreich M., Antonakos N., Nuesch-Germano M., Gkizeli K., Bonaguro L., Reusch N., Baßler K., et al. Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. Genome Med. 2021;13:7. doi: 10.1186/s13073-020-00823-5. - DOI - PMC - PubMed

[5] Meizlish M.L., Pine A.B., Bishai J.D., Goshua G., Nadelmann E.R., Simonov M., Chang C.H., Zhang H., Shallow M., Bahel P., et al. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv. 2021;5:1164–1177. doi: 10.1182/bloodadvances.2020003568. - DOI - PMC - PubMed

[6] Meizlish M.L., Pine A.B., Bishai J.D., Goshua G., Nadelmann E.R., Simonov M., Chang C.H., Zhang H., Shallow M., Bahel P., et al. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv. 2021;5:1164–1177. doi: 10.1182/bloodadvances.2020003568. - DOI - PMC - PubMed

[7] Schulte-Schrepping J., Reusch N., Paclik D., Baßler K., Schlickeiser S., Zhang B., Krämer B., Krammer T., Brumhard S., Bonaguro L., et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182:1419–1440.e23. doi: 10.1016/j.cell.2020.08.001. e1423. - DOI - PMC - PubMed

[8] Schulte-Schrepping J., Reusch N., Paclik D., Baßler K., Schlickeiser S., Zhang B., Krämer B., Krammer T., Brumhard S., Bonaguro L., et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182:1419–1440.e23. doi: 10.1016/j.cell.2020.08.001. e1423. - DOI - PMC - PubMed

[9] CDC . 2021. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C)https://www.cdc.gov/mis/mis-c/hcp/index.html

[10] CDC . 2021. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C)https://www.cdc.gov/mis/mis-c/hcp/index.html

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

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

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