Clinical and Translational Article A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inﬂammatory syndrome in children with severe myocarditis

Multiparametric analysis identiﬁes, in monocytes and dendritic cells, a molecular signature of the most severe forms of multisystem inﬂammatory syndrome in children caused by SARS-CoV-2 infection. Severe myocarditis is characterized by an excess of TNF- a signaling via NF- k B, hypoxic conditions, and hyperinﬂammation in the absence of type I and type II interferon responses. Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in To further decipher SARS-CoV-2-related conditions in children, we performed a detailed multiparametric study combining sensitive cytokine measurements, deep immune cell phenotyping, and transcriptomics analyses at the single-cell level on peripheral blood mononuclear cells (PBMCs). We ﬁrst compared data from children with SARS-CoV-2 acute infection and postacute hyperinﬂammation and then analyzed pathways and molecular signatures characteristic of the most severe form of MIS-C with severe myocarditis. in acute infection or postacute hyperinﬂammatory illness reﬂected an inﬂammatory status based on NF- k B signaling combined with changes in metabolism driven by a hypoxic environment. In acute respiratory disease, changes in gene expression reﬂected involvement of all PBMCs, whereas in postacute hyperinﬂammatory illnesses, monocytes/DCs were the most affected populations. These results further support involvement of monocyte/DC populations in MIS-C. pathways that were found speciﬁcally in monocytes and DCs of individuals with MIS-C with severe myocarditis. Lower expression of NF- k B complex inhibitors, including TNFAIP3 (A20), TNFAIP2 , NFKBIA , and NFKBIZ , was detected, suggesting a possible mechanism for NF- k B sustained activation, which could then potentially lead to exacerbated TNF- a signaling. These results point to a potential role of monocytes and DCs in the pathogenesis of MIS-C with severe myocarditis, which might not be driven directly by SARS-CoV-2 infection but, rather, the consequence of a defect in a regulatory process limiting a pathological immune response, as already observed for other pathogens. 43 It would be interesting to investigate the presence of genetic variants among MIS-C with severe myocarditis in genes such as TNFAIP3 , as discussed previously. 43 The apparent hypoxic conditions in children myocarditis could also account for the exacerbation of NF- k B signaling. HIF-1 a , sensor well induce a switch from phosphorylation limit of reactive oxygen species (ROS). can also activate NF- k B signaling. 44,45 Additional environmental factors and/or genetic predispositions could also be involved. Another striking feature was the low expression of genes involved in type I and type II IFN responses, speciﬁcally in monocytes and DCs of children with myocarditis, although IFN- g and IFN- a 2 proteins were elevated in the plasma of all individuals with MIS-C. Although an absence of type II IFN responses could account for reduced Human Leucocyte Antigen-DR (HLA-DR) cell surface expression by monocytes/DCs, the reduced response to type I IFN in the most severe forms of MIS-C (with myocarditis and circulatory failure) is in part reminiscent of the impaired type I IFN activity observed in the most severe forms of COVID-19 in adults. and open new therapeutic strategies, including drugs targeting the TNF- a or NF- k B pathways.