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., ...More

Science, vol.379, no.6632, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 379 Issue: 6632
  • Publication Date: 2023
  • Doi Number: 10.1126/science.abo3627
  • Journal Name: Science
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Applied Science & Technology Source, Aquatic Science & Fisheries Abstracts (ASFA), Artic & Antarctic Regions, ATLA Religion Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, Computer & Applied Sciences, EBSCO Education Source, EMBASE, Environment Index, Gender Studies Database, Geobase, Linguistic Bibliography, MEDLINE, Metadex, MLA - Modern Language Association Database, Pollution Abstracts, Psycinfo, Public Affairs Index, Veterinary Science Database, zbMATH, DIALNET, Civil Engineering Abstracts
  • Karadeniz Technical University Affiliated: Yes

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.