Abstract
Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.
Highlights
Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation, and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection[1,2,3]
RNA-seq was performed on 30 whole-blood specimens from MIS-C cases, pediatric COVID-19 cases (18 specimens from seven individuals), and healthy controls (HCs; four specimens from four individuals) collected as part of their clinical visits (Fig. 1a, Table 1, Supplementary Data 1–3, see the “Methods” section)
Quality control procedures identified eight covariates driving variance in gene expression, which were accounted for in subsequent analyses (Supplementary Fig. 1a–d). One of these covariates was age, which was mismatched between cases and controls due to the circumstances of the current pandemic. It was modeled by deriving an estimate of the transcriptional age of each study participant
Summary
RNA-seq was performed on 30 whole-blood specimens from MIS-C cases (eight specimens from eight individuals), pediatric COVID-19 cases (18 specimens from seven individuals), and healthy controls (HCs; four specimens from four individuals) collected as part of their clinical visits (Fig. 1a, Table 1, Supplementary Data 1–3, see the “Methods” section). Deconvolution identified cytotoxic T cells as significantly downregulated in MIS-C compared to HCs, and Bcells as significantly downregulated in pediatric COVID-19 cases compared to MIS-C cases and upregulated in pediatric COVID19 cases compared to HCs (Supplementary Fig. 3, Supplementary Data 5 and 6, see the “Methods” section). To identify known biological processes associated with MIS-C and pediatric COVID-19, we tested these three upregulated and downregulated DE signatures for the enrichment of canonical pathways (Fig. 2c and Supplementary Data 8). The module most significantly impacted in MIS-C was skyblue (159 genes; Fisher’s exact test odds ratio [OR] for downregulated MIS-C DEGs = 23.44, adjusted p-value = 4.33E −66) This module was annotated to CD8+ T cells and NK cells, the cornerstones of cytotoxic immunity, corroborating the observations from cell type deconvolution described above (Fig. 3b, Supplementary Fig. 4, and Supplementary Data 10–12; see the “Methods” section). MIS-C (N=8) Pediatric COVID-19 (N-7, up to 5 time points) Healthy Controls (N=4)
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