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A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis #MMPMID34414385
de Cevins C; Luka M; Smith N; Meynier S; Magerus A; Carbone F; Garcia-Paredes V; Barnabei L; Batignes M; Boulle A; Stolzenberg MC; Perot BP; Charbit B; Fali T; Pirabakaran V; Sorin B; Riller Q; Abdessalem G; Beretta M; Grzelak L; Goncalves P; Di Santo JP; Mouquet H; Schwartz O; Zarhrate M; Parisot M; Bole-Feysot C; Masson C; Cagnard N; Corneau A; Brunaud C; Zhang SY; Casanova JL; Bader-Meunier B; Haroche J; Melki I; Lorrot M; Oualha M; Moulin F; Bonnet D; Belhadjer Z; Leruez M; Allali S; Gras-Leguen C; de Pontual L; Fischer A; Duffy D; Rieux-Laucat F; Toubiana J; Menager MM
Med 2021[Sep]; 2 (9): 1072-1092.e7 PMID34414385show ga
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 kappaB (NF-kappaB) activity and tumor necrosis factor alpha (TNF-alpha) signaling and associated with decreased gene expression of NF-kappaB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1alpha 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 Interieur," grant ANR-10-LABX-69-01; ANR-flash Covid19 "AIROCovid" and "CoVarImm"), Institut National de la Sante et de la Recherche Medicale (INSERM), and the "URGENCE COVID-19" fundraising campaign of Institut Pasteur.