Med
Volume 2, Issue 9, 10 September 2021, Pages 1072-1092.e7
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Clinical and Translational Article
A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis

https://doi.org/10.1016/j.medj.2021.08.002Get rights and content
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Highlights

  • Hyperinflammatory cytokines coupled with decrease in monocytes, cDCs, pDCs in MIS-C

  • A molecular signature in monocytes can discriminate MIS-C with severe myocarditis

  • It consists of exacerbated TNF-α signaling linked with decreased NF-κB inhibitors

  • This is observed in parallel to an absence of type I and type II IFN responses

Context and significance

Children with SARS-CoV-2 infection were initially thought to have only mild COVID-19 symptoms. However, several weeks into the first wave of SARS-CoV-2 infections, there was a surge of a postacute pathology called multisystem inflammatory syndrome in children (MIS-C). The authors recruited a cohort of children with suspicion of SARS-CoV-2 infection and uncovered hyperinflammation, hypoxic conditions, exacerbation of TNF-α signaling via NF-κB, and absence of responses to type I and type II IFN secretion in the most severe forms of MIS-C with severe myocarditis. This work led the authors to identify in monocytes and validate in peripheral blood mononuclear cells a molecular signature of 25 genes that allows discrimination of the most severe forms of MIS-C with myocarditis.

Summary

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis.

Methods

To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels.

Findings

The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling.

Conclusions

These results provide potential for a better understanding of disease pathophysiology.

Funding

Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d’Excellence ‘‘Milieu Intérieur,” grant ANR-10-LABX-69-01; ANR-flash Covid19 “AIROCovid” and “CoVarImm”), Institut National de la Santé et de la Recherche Médicale (INSERM), and the “URGENCE COVID-19” fundraising campaign of Institut Pasteur.

Keywords

COVID-19
SARS-CoV-2
scRNA-seq
MIS-C
PIMS-TS
Kawasaki Disease
myocarditis
TNF-α and NF-κB signaling
lack of responses to type I and type II IFN secretion

CAT scale

Translation to patients

Data and code availability

Single-cell and bulk RNA-seq data have been deposited in GEO and are publicly available. Accession numbers are listed in the key resources table. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Lead contact