Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children. Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children

Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by SARS-CoV-2 antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that the hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature. Overall design: Gene expression profiling analysis using bulk RNA-seq data of neutrophils enriched from fresh whole blood of 19 children with acute COVID-19, 17 children with MIS-C, and 12 pediatric controls.

儿童多系统炎症综合征（Multisystem Inflammatory Syndrome in Children, MIS-C）是一种迟发性、与新型冠状病毒肺炎（COVID-19）相关的高炎症性疾病，以新型冠状病毒（SARS-CoV-2）抗原血症、细胞因子风暴及免疫失调为特征。在重型COVID-19中，中性粒细胞活化是高炎症并发症的核心环节，但中性粒细胞在MIS-C中的作用尚未明确。本研究收集了152名儿童的血液样本：其中31例MIS-C患者、43例儿童急性COVID-19患者，以及78名儿童健康对照。研究发现，MIS-C患者的中性粒细胞呈现出粒细胞性髓系来源抑制细胞（granulocytic myeloid-derived suppressor cell, G-MDSC）特征，且代谢状态发生显著改变，这与我们在儿童COVID-19中观察到的中性粒细胞干扰素刺激基因（interferon-stimulated gene, ISG）应答截然不同。此外，我们在MIS-C中观察到广泛的自发性中性粒细胞胞外陷阱（neutrophil extracellular trap, NET）形成，并鉴定出中性粒细胞活化与脱颗粒特征。机制层面上，我们证实新型冠状病毒免疫复合物足以诱导中性粒细胞胞外陷阱形成（NETosis）。本研究结果提示，MIS-C的高炎症表型可能与持续性SARS-CoV-2抗原血症存在机制关联，该过程由血管中不受控的中性粒细胞活化及NET释放所驱动。整体实验设计：对19例急性COVID-19儿童、17例MIS-C儿童及12名儿童健康对照的新鲜全血富集中性粒细胞进行批量RNA测序（bulk RNA-seq）的基因表达谱分析。