PRJNA764084: Single cell RNA sequencing and TCR repertoire analysis of MIS-C affected patients versus healthy controls and severe adult COVID-19

Summary: In rare instances, pediatric SARS-CoV2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with that of severe COVID-19. MIS-C does not result in pneumocyte damage but is associated with vascular endothelitis, gastrointestinal epithelial injury and endotoxemia. In MIS-C, IFN dominates the inflammatory signature in contrast to type I interferons in severe COVID-19. MIS-C does not result in pneumocyte damage but is associated with vascular endothelitis, gastrointestinal epithelial injury and endotoxemia. In MIS-C, IFN dominates the inflammatory signature in contrast to type I interferons in severe COVID-19. While HLA-DRlo classical monocytes dominate severe COVID-19, patrolling monocyte activation characterize MIS-C. TIM-3 expression on activated CD4/CD8  T cells and on CD57+ NK cells is a distinctive MIS-C feature. In all MIS-C patients, single cell TCR profiling demonstrates a skewed TCR repertoire enriched for TRBV11-2 and a superantigenic signature which is absent in severe COVID-19. Using NicheNet, we confirm IFN as a central cytokine in the communication between activated T cells, NK cells and patrolling monocytes. Rapid normalization of IFN, TIM-3 loss on T cells and patrolling monocytes contraction upon treatment highlight their potential role in MIS-C immunopathogenesis.

Overall Design: Single cell RNA sequencing of 7 pediatric patients suffering from MIS-C, compared with 5 healthy siblings that did not experience MIS-C, and 4 adult patients with severe COVID-19. Patient samples were obtained during hospitalisation and at maximal inflammation. Samples from siblings were acquired ambulatory in the absence of inflammation. We compared transcriptomic data in leukocytes between these three cohorts and used additional computational modelling tools (GSEA, IPA and Nichenet) to characterize the immunodysregulation that is observed in MIS-C and is distinct from baseline conditions in their healthy siblings and adult COVID-19. In addition, we specifically analyzed the TCR repertoire within the T cells of these patients.