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

, , Jessica Peel, Yi-Hao Chan, Marie-Paule Morin, Rosa Maria Pino-Ramirez, Serkan Belkaya, Lazaro Lorenzo, Jordi Anton, Selket Delafontaine, Julie Toubiana, Fanny Bajolle, Victoria Fumadó, Marta L. DeDiego, Nadhira Fidouh, Flore Rozenberg, Jordi Pérez-Tur, Shuibing hen, Todd Evans, Frédéric GeissmannPierre Lebon, Susan R. Weiss, Damien Bonnet, Xavier Duval, Qiang Pan-Hammarström, Anna M. Planas, Isabelle Meyts, Filomeen Haerynck, Aurora Pujol, Vanessa Sancho-Shimizu, Clifford L. Dalgard, Jacinta Bustamante, Anne Puel, Stéphanie Boisson-Dupuis, Bertrand Boisson, Tom Maniatis, Qian Zhang, Paul Bastard, Luigi Notarangelo, Vivien Béziat, Rebeca Perez de Diego, Carlos Rodriguez-Gallego, Helen C. Su, Richard P. Lifton, Emmanuelle Jouanguy, Aurélie Cobat, Laia Alsina, Sevgi Keles, Elie Haddad, Laurent Abel, Alexandre Belot, Lluis Quintana-Murci, Charles M. Rice, Robert H. Silverman, Shen-Ying Zhang, Jean-Laurent Casanova, Roger Colobran Oriol, Agustin Rodriguez Palmero Seuma

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Resum

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.
Idioma originalAnglès
Número d’articleeabo3627
Nombre de pàgines21
RevistaScience
Volum379
Número6632
DOIs
Estat de la publicacióPublicada - 10 de febr. 2023

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