Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Lee, Danyel; COVID Human Genetic Effort; Zhang, Shen-Ying

doi:http://dx.doi.org/10.1126/science.abo3627

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

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Lee D, Le Pen J, Yatim A, Dong B, Aquino Y, Ogishi M, et al. Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children. Science. 2023 Feb 10;379(6632):eabo3627. DOI: 10.1126/science.abo3627

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL 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.