A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis [Single cell RNAseq]. A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis [Single cell RNAseq]

SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of myocarditis, characterized by sustained NF-kB activity, associated with decreased gene expression of NF-kB inhibitors and TNF-a signaling . We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1a and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology. Overall design: scRNAseq on PBMC from 9 CTL (two of which had replicates), 1 Acute-Inf (CoV2-), 4 Acute-Inf (CoV2+), 2 MIS-C (CoV2+), 6 MIS-C_MYO (CoV2+) and 2 KD (CoV2-)

儿童感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）后的病情通常较成人轻微，但仍有部分病例会进展为过度炎症状态，常伴随心肌炎。为深入探究此类病例的发病机制，我们针对56例因疑似SARS-CoV-2感染住院的儿童的血细胞样本采用多参数研究方法展开分析。以合并心肌炎的儿童多系统炎症综合征（multisystem inflammatory syndrome in children related to SARS-CoV-2，MIS-C）的最严重亚型为例，其特征为促血管生成细胞因子与多种趋化因子水平显著升高。单细胞转录组分析鉴定出一种独特的单核细胞/树突状细胞基因特征，该特征与心肌炎的发生密切相关：核因子κB（NF-κB）活性持续上调，同时伴随核因子κB抑制剂及肿瘤坏死因子α（TNF-α）信号通路相关基因的表达下调。我们还发现I型和II型干扰素应答较弱，同时存在过度炎症状态，且氧化应激应答与缺氧诱导因子1α（HIF-1α）、血管内皮生长因子（VEGF）信号通路的增强相关。本研究结果为深入理解该疾病的病理生理机制提供了重要理论依据。整体实验设计如下：对9例健康对照（CTL，其中2例设有生物学重复）、1例急性感染组（新冠病毒检测阴性，Acute-Inf（CoV2-））、4例急性感染组（新冠病毒检测阳性，Acute-Inf（CoV2+））、2例儿童多系统炎症综合征组（新冠病毒检测阳性，MIS-C（CoV2+））、6例合并心肌炎的儿童多系统炎症综合征组（新冠病毒检测阳性，MIS-C_MYO（CoV2+））以及2例川崎病组（新冠病毒检测阴性，KD（CoV2-））的外周血单个核细胞（PBMC）开展单细胞RNA测序（scRNAseq）