St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Science. 2023 Feb 10;379(6632):eabo3627. doi: 10.1126/science.abo3627.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of , , or in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
儿童多系统炎症综合征（MIS-C）是一种罕见且严重的疾病，紧随良性 COVID-19 之后。我们报告了五例无关的 MIS-C 患儿存在常染色体隐性遗传的 、 或 缺陷。细胞质双链 RNA（dsRNA）感应 OAS1 和 OAS2 生成 2'-5'-连接寡腺苷酸（2-5A），激活单链 RNA 降解核糖核酸酶 L（RNase L）。OAS1、OAS2 或 RNase L 缺陷的单核细胞系和原代髓样细胞在 dsRNA 或严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）刺激下产生过量的炎症细胞因子。外源性 2-5A 可抑制 OAS1 缺陷但不抑制 RNase L 缺陷细胞中的细胞因子产生。MDA5 或 RIG-I 缺陷可损害 RNase L 缺陷细胞中的细胞因子产生，而线粒体抗病毒信号蛋白（MAVS）缺陷则可消除该缺陷。这些患者的隐性 OAS-RNase L 缺陷可引发单核吞噬细胞产生 SARS-CoV-2 触发的 MAVS 介导的炎症细胞因子，从而导致 MIS-C。
