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other·pediatrics, immunology, infectious disease, biomedical research·PMC10451000

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

Science (New York, N.y.) · 102 authors, 81 centres

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TL;DR

This study identified autosomal recessive deficiencies in OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. Gene-edited cell lines and patient-derived myeloid cells showed that these deficiencies cause excessive inflammatory cytokine production upon SARS-CoV-2 or dsRNA stimulation via a MAVS-dependent mechanism.

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Five unrelated children presenting with MIS-C were found to harbor autosomal recessive loss-of-function variants in OAS1, OAS2, or RNASEL. The authors used THP-1 monocytic cell lines with gene knockouts and patient-derived peripheral blood mononuclear cells to characterize the immunological consequences. OAS1, OAS2, or RNase L-deficient THP-1 cells produced elevated inflammatory cytokines—including IL-6, TNF, CXCL10, and IFN-λ1—upon intracellular dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppressed cytokine production in OAS1-deficient but not RNase L-deficient cells. In RNase L-deficient cells, cytokine overproduction was impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency, implicating the cytosolic RNA sensing–MAVS axis. These findings suggest that recessive OAS–RNase L deficiencies unleash SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokine production by mononuclear phagocytes, underlying MIS-C.

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other

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pediatrics

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ORIGINAL PAPER

PMC10451000

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

Science (New York, N.y.)

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ABSTRACT

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.

CITATION EXPORT

Danyel Lee, Jérémie Le Pen, Ahmad Yatim et al.. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children. Science (New York, N.y.). (2023). https://doi.org/10.1126/science.abo3627

AUTHORS

102 · 81 CENTRES

Danyel Lee, Jérémie Le Pen, Ahmad Yatim, Beihua Dong, Yann Aquino, Masato Ogishi, Rémi Pescarmona, Estelle Talouarn, Darawan Rinchai, Peng Zhang, Magali Perret, Zhiyong Liu, Iolanda Jordan, Sefika Elmas Bozdemir, Gulsum Iclal Bayhan, Camille Beaufils, Lucy Bizien, Aurelie Bisiaux, Weite Lei, Milena Hasan, Jie Chen, Christina Gaughan, Abhishek Asthana, Valentina Libri, Joseph M Luna, Fabrice Jaffré, H-Heinrich Hoffmann, Eleftherios Michailidis, Marion Moreews, Yoann Seeleuthner, Kaya Bilguvar, Shrikant Mane, Carlos Flores, Yu Zhang, Andrés A Arias, Rasheed Bailey, Agatha Schlüter, Baptiste Milisavljevic, Benedetta Bigio, Tom Le Voyer, Marie Materna, Adrian Gervais, Marcela Moncada-Velez, Francesca Pala, Tomi Lazarov, Romain Levy, Anna-Lena Neehus, Jérémie Rosain, 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 Chen, Todd Evans, Frédéric Geissmann, Pierre 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

1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
2Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
3Paris City University, Imagine Institute, Paris, France.
4Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
5Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
6Human Evolutionary Genetics Unit, Institut Pasteur, Paris City University, CNRS UMR 2000, Paris, France.
7Doctoral College, Sorbonne University, Paris, France.
8Laboratory of Immunology, Lyon Sud Hospital, Lyon, France.
9Pediatric Intensive Care Department, Hospital Sant Joan de Déu, Barcelona, Spain.
10Kids Corona Platform, Barcelona, Spain.
11Center for Biomedical Network Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.
12Department of Surgery and Surgical Specializations, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
13Respiratory and Immunological Dysfunction in Pediatric Critically Ill Patients, Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
14Bursa City Hospital, Bursa, Turkey.
15Ankara City Hospital, Yildirim Beyazit University, Ankara, Turkey.
16Immunology and Rheumatology Division, Department of Pediatrics, University of Montreal, CHU Sainte-Justine, Montreal, QC, Canada.
17Center for Translational Research, Institut Pasteur, Paris City University, Paris, France.
18Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, USA.
19Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
20Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
21International Center of Infectiology Research (CIRI), University of Lyon, INSERM U1111, Claude Bernard University, Lyon 1, CNRS, UMR5308, ENS of Lyon, Lyon, France.
22Departments of Neurosurgery and Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
23Department of Medical Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
24Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
25Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain.
26Genomics Division, Institute of Technology and Renewable Energies (ITER), Granadilla de Abona, Spain.
27CIBERES, ISCIII, Madrid, Spain.
28Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
29Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
30NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
31Primary Immunodeficiencies Group, University of Antioquia (UdeA), Medellin, Colombia.
32School of Microbiology, University of Antioquia (UdeA), Medellin, Colombia.
33Neurometabolic Diseases Laboratory, IDIBELL–Hospital Duran I Reynals, CIBERER U759, ISIiii, Madrid, Spain.
34Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
35Pediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
36Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
37Pediatric Rheumatology Division, Hospital Sant Joan de Déu, Barcelona, Spain.
38Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
39Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
40Department of General Pediatrics and Pediatric Infectious Diseases, Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris City University, Paris, France.
41Biodiversity and Epidemiology of Bacterial Pathogens, Pasteur Institute, Paris, France.
42Department of Pediatric Cardiology, Necker Hospital for Sick Children, AP-HP, Paris City University, Paris, France.
43Pediatrics Infectious Diseases Division, Hospital Sant Joan de Déu, Barcelona, Spain.
44Infectious Diseases and Microbiome, Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
45Department of Molecular and Cellular Biology, National Center for Biotechnology (CNB-CSIC), Madrid, Spain.
46Laboratory of Virology, Bichat–Claude Bernard Hospital, Paris, France.
47Laboratory of Virology, AP-HP, Cochin Hospital, Paris, France.
48Molecular Genetics Unit, Institute of Biomedicine of Valencia (IBV-CSIC), Valencia, Spain.
49CIBERNED, ISCIII, Madrid, Spain.
50Joint Research Unit in Neurology and Molecular Genetics, Institut of Investigation Sanitaria La Fe, Valencia, Spain.
51Medical School, Paris City University, Paris, France.
52Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
53Bichat–Claude Bernard Hospital, Paris, France.
54University Paris Diderot, Paris 7, UFR of Médecine-Bichat, Paris, France.
55IAME, INSERM, UMRS1137, Paris City University, Paris, France.
56Infectious and Tropical Diseases Department, AP-HP, Bichat–Claude Bernard Hospital, Paris, France.
57Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
58Department of Neuroscience and Experimental Therapeutics, Institute for Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain.
59Institute for Biomedical Investigations August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
60Department of Pediatrics, University Hospitals Leuven and Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
61Primary Immunodeficiency Research Laboratory, Center for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, Belgium.
62Neurometabolic Diseases Laboratory, IDIBELL–Hospital Duran I Reynals; and Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
63CIBERER U759, ISCiii, Madrid, Spain.
64Department of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK.
65Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
66The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
67Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
68Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France.
69New York Genome Center, New York, NY, USA.
70Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
71Laboratory of Immunogenetics of Human Diseases, Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.
72Interdepartmental Group of Immunodeficiencies, Madrid, Spain.
73Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
74Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
75Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
76Necmettin Erbakan University, Konya, Turkey.
77Department of Pediatrics, Department of Microbiology, Immunology and Infectious Diseases, University of Montreal and Immunology and Rheumatology Division, CHU Sainte-Justine, Montreal, QC, Canada.
78National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Pediatric Nephrology, Rheumatology, Dermatology Unit, Hospital of Mother and Child, Hospices Civils of Lyon, Lyon, France.
79Human Genomics and Evolution, Collège de France, Paris, France.
80Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
81Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.