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.
Danyel Lee  1  2  3 ,  Jérémie Le Pen  #  4 ,  Ahmad Yatim  #  1 ,  Beihua Dong  #  5 ,  Yann Aquino  #  6  7 ,  Masato Ogishi  #  1 ,  Rémi Pescarmona  #  8 ,  Estelle Talouarn  #  2  3 ,  Darawan Rinchai  #  1 ,  Peng Zhang  #  1 ,  Magali Perret  #  8 ,  Zhiyong Liu  1 ,  Iolanda Jordan  9  10  11  12  13 ,  Sefika Elmas Bozdemir  14 ,  Gulsum Iclal Bayhan  15 ,  Camille Beaufils  16 ,  Lucy Bizien  2  3 ,  Aurelie Bisiaux  6 ,  Weite Lei  1 ,  Milena Hasan  17 ,  Jie Chen  1 ,  Christina Gaughan  5 ,  Abhishek Asthana  5 ,  Valentina Libri  17 ,  Joseph M Luna  4  18 ,  Fabrice Jaffré  19 ,  H-Heinrich Hoffmann  4 ,  Eleftherios Michailidis  4  20 ,  Marion Moreews  21 ,  Yoann Seeleuthner  2  3 ,  Kaya Bilguvar  22  23 ,  Shrikant Mane  24 ,  Carlos Flores  25  26  27 ,  Yu Zhang  28  29 ,  Andrés A Arias  1  30  31 ,  Rasheed Bailey  1 ,  Agatha Schlüter  32 ,  Baptiste Milisavljevic  1 ,  Benedetta Bigio  1 ,  Tom Le Voyer  2  3 ,  Marie Materna  2  3 ,  Adrian Gervais  2  3 ,  Marcela Moncada-Velez  1 ,  Francesca Pala  28 ,  Tomi Lazarov  33 ,  Romain Levy  2  3 ,  Anna-Lena Neehus  2  3 ,  Jérémie Rosain  2  3 ,  Jessica Peel  1 ,  Yi-Hao Chan  1 ,  Marie-Paule Morin  16 ,  Rosa Maria Pino-Ramirez  34 ,  Serkan Belkaya  35 ,  Lazaro Lorenzo  1 ,  Jordi Anton  12  36  37 ,  Selket Delafontaine  38 ,  Julie Toubiana  39  40 ,  Fanny Bajolle  41 ,  Victoria Fumadó  10  12  42  43 ,  Marta L DeDiego  44 ,  Nadhira Fidouh  45 ,  Flore Rozenberg  46 ,  Jordi Pérez-Tur  47  48  49 ,  Shuibing Chen  19 ,  Todd Evans  19 ,  Frédéric Geissmann  33 ,  Pierre Lebon  50 ,  Susan R Weiss  51 ,  Damien Bonnet  41 ,  Xavier Duval  52  53  54  55 ,  CoV-Contact Cohort§ ,  COVID Human Genetic Effort¶ ,  Qiang Pan-Hammarström  56 ,  Anna M Planas  57  58 ,  Isabelle Meyts  59 ,  Filomeen Haerynck  60 ,  Aurora Pujol  61  62 ,  Vanessa Sancho-Shimizu  63  64 ,  Clifford L Dalgard  65  66 ,  Jacinta Bustamante  1  2  3  67 ,  Anne Puel  1  2  3 ,  Stéphanie Boisson-Dupuis  1  2  3 ,  Bertrand Boisson  1  2  3 ,  Tom Maniatis  68 ,  Qian Zhang  1  2  3 ,  Paul Bastard  1  2  3  69 ,  Luigi Notarangelo  28 ,  Vivien Béziat  1  2  3 ,  Rebeca Perez de Diego  70  71 ,  Carlos Rodriguez-Gallego  72  73 ,  Helen C Su  28  29 ,  Richard P Lifton  24  74 ,  Emmanuelle Jouanguy  1  2  3 ,  Aurélie Cobat  #  1  2  3 ,  Laia Alsina  #  10  12  37  75 ,  Sevgi Keles  #  76 ,  Elie Haddad  #  77 ,  Laurent Abel  #  1  2  3 ,  Alexandre Belot  #  21  78 ,  Lluis Quintana-Murci  #  6  79 ,  Charles M Rice  #  4 ,  Robert H Silverman  #  5 ,  Shen-Ying Zhang  #  1  2  3 ,  Jean-Laurent Casanova  #  1  2  3  80  81
Affiliations
  • 1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
  • 3. Paris City University, Imagine Institute, Paris, France.
  • 4. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • 5. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 6. Human Evolutionary Genetics Unit, Institut Pasteur, Paris City University, CNRS UMR 2000, Paris, France.
  • 7. Doctoral College, Sorbonne University, Paris, France.
  • 8. Laboratory of Immunology, Lyon Sud Hospital, Lyon, France.
  • 9. Pediatric Intensive Care Department, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 10. Kids Corona Platform, Barcelona, Spain.
  • 11. Center for Biomedical Network Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.
  • 12. Department of Surgery and Surgical Specializations, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
  • 13. Respiratory and Immunological Dysfunction in Pediatric Critically Ill Patients, Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
  • 14. Bursa City Hospital, Bursa, Turkey.
  • 15. Ankara City Hospital, Yildirim Beyazit University, Ankara, Turkey.
  • 16. Immunology and Rheumatology Division, Department of Pediatrics, University of Montreal, CHU Sainte-Justine, Montreal, QC, Canada.
  • 17. Center for Translational Research, Institut Pasteur, Paris City University, Paris, France.
  • 18. Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, USA.
  • 19. Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
  • 20. Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
  • 21. International Center of Infectiology Research (CIRI), University of Lyon, INSERM U1111, Claude Bernard University, Lyon 1, CNRS, UMR5308, ENS of Lyon, Lyon, France.
  • 22. Departments of Neurosurgery and Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
  • 23. Department of Medical Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
  • 24. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • 25. Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain.
  • 26. Genomics Division, Institute of Technology and Renewable Energies (ITER), Granadilla de Abona, Spain.
  • 27. CIBERES, ISCIII, Madrid, Spain.
  • 28. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
  • 29. NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
  • 30. Primary Immunodeficiencies Group, University of Antioquia (UdeA), Medellin, Colombia.
  • 31. School of Microbiology, University of Antioquia (UdeA), Medellin, Colombia.
  • 32. Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran I Reynals, CIBERER U759, ISIiii, Madrid, Spain.
  • 33. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 34. Pediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 35. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
  • 36. Pediatric Rheumatology Division, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 37. Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
  • 38. Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
  • 39. Department of General Pediatrics and Pediatric Infectious Diseases, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris City University, Paris, France.
  • 40. Biodiversity and Epidemiology of Bacterial Pathogens, Pasteur Institute, Paris, France.
  • 41. Department of Pediatric Cardiology, Necker Hospital for Sick Children, AP-HP, Paris City University, Paris, France.
  • 42. Pediatrics Infectious Diseases Division, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 43. Infectious Diseases and Microbiome, Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
  • 44. Department of Molecular and Cellular Biology, National Center for Biotechnology (CNB-CSIC), Madrid, Spain.
  • 45. Laboratory of Virology, Bichat-Claude Bernard Hospital, Paris, France.
  • 46. Laboratory of Virology, AP-HP, Cochin Hospital, Paris, France.
  • 47. Molecular Genetics Unit, Institute of Biomedicine of Valencia (IBV-CSIC), Valencia, Spain.
  • 48. CIBERNED, ISCIII, Madrid, Spain.
  • 49. Joint Research Unit in Neurology and Molecular Genetics, Institut of Investigation Sanitaria La Fe, Valencia, Spain.
  • 50. Medical School, Paris City University, Paris, France.
  • 51. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 52. Bichat-Claude Bernard Hospital, Paris, France.
  • 53. University Paris Diderot, Paris 7, UFR of Médecine-Bichat, Paris, France.
  • 54. IAME, INSERM, UMRS1137, Paris City University, Paris, France.
  • 55. Infectious and Tropical Diseases Department, AP-HP, Bichat-Claude Bernard Hospital, Paris, France.
  • 56. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
  • 57. Department of Neuroscience and Experimental Therapeutics, Institute for Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain.
  • 58. Institute for Biomedical Investigations August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • 59. Department of Pediatrics, University Hospitals Leuven and Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
  • 60. Primary Immunodeficiency Research Laboratory, Center for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, Belgium.
  • 61. Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran I Reynals; and Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
  • 62. CIBERER U759, ISCiii, Madrid, Spain.
  • 63. Department of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK.
  • 64. Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
  • 65. The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 66. Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 67. Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 68. New York Genome Center, New York, NY, USA.
  • 69. Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 70. Laboratory of Immunogenetics of Human Diseases, Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.
  • 71. Interdepartmental Group of Immunodeficiencies, Madrid, Spain.
  • 72. Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
  • 73. Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
  • 74. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • 75. Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 76. Necmettin Erbakan University, Konya, Turkey.
  • 77. Department of Pediatrics, Department of Microbiology, Immunology and Infectious Diseases, University of Montreal and Immunology and Rheumatology Division, CHU Sainte-Justine, Montreal, QC, Canada.
  • 78. National 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.
  • 79. Human Genomics and Evolution, Collège de France, Paris, France.
  • 80. Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
  • 81. Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
  • # Contributed equally.
PMID: 36538032 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.