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

• Type of Material: Article
• Authors: Danyel Lee, Rockefeller University; Jeremie Le Pen, Rockefeller University; Ahmad Yatim, Rockefeller University; Beihua Dong, Cleveland Clinic; Yann Aquino, Paris City University; Eleftherios Michailidis, Emory University
• Language: English
• Date: 2023-02-10
• Publisher: AAAS
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1126%2Fscience.abo3627
• Title of Journal or Parent Work: Science
• Volume: 379
• Issue: 6632
• Start Page: eabo3627
• Grant/Funding Information: See publication for full funding statement.
• Keywords: OAS1; OAS2; autosomal recessive deficiencies; COVID-19; Multisystem inflammatory syndrome in children (MIS-C); RNASEL
• Research Categories: Biology, Virology

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.