Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children
Author:
Lee Danyel123ORCID, Le Pen Jérémie4ORCID, Yatim Ahmad1, Dong Beihua5, Aquino Yann67ORCID, Ogishi Masato1ORCID, Pescarmona Rémi8ORCID, Talouarn Estelle23ORCID, Rinchai Darawan1ORCID, Zhang Peng1ORCID, Perret Magali8ORCID, Liu Zhiyong1ORCID, Jordan Iolanda910111213ORCID, Elmas Bozdemir Sefika14ORCID, Bayhan Gulsum Iclal15ORCID, Beaufils Camille16ORCID, Bizien Lucy23ORCID, Bisiaux Aurelie6ORCID, Lei Weite1ORCID, Hasan Milena17, Chen Jie1, Gaughan Christina5ORCID, Asthana Abhishek5ORCID, Libri Valentina17ORCID, Luna Joseph M.418ORCID, Jaffré Fabrice19ORCID, Hoffmann H.-Heinrich4ORCID, Michailidis Eleftherios420ORCID, Moreews Marion21ORCID, Seeleuthner Yoann23, Bilguvar Kaya2223ORCID, Mane Shrikant24ORCID, Flores Carlos252627ORCID, Zhang Yu2829ORCID, Arias Andrés A.13031ORCID, Bailey Rasheed1, Schlüter Agatha32ORCID, Milisavljevic Baptiste1, Bigio Benedetta1, Le Voyer Tom23ORCID, Materna Marie23ORCID, Gervais Adrian23ORCID, Moncada-Velez Marcela1ORCID, Pala Francesca28ORCID, Lazarov Tomi33ORCID, Levy Romain23ORCID, Neehus Anna-Lena23ORCID, Rosain Jérémie23ORCID, Peel Jessica1, Chan Yi-Hao1ORCID, Morin Marie-Paule16, Pino-Ramirez Rosa Maria34ORCID, Belkaya Serkan35ORCID, Lorenzo Lazaro1ORCID, Anton Jordi123637ORCID, Delafontaine Selket38ORCID, Toubiana Julie3940, Bajolle Fanny41ORCID, Fumadó Victoria10124243, DeDiego Marta L.44, Fidouh Nadhira45, Rozenberg Flore46, Pérez-Tur Jordi474849ORCID, Chen Shuibing19ORCID, Evans Todd19ORCID, Geissmann Frédéric33ORCID, Lebon Pierre50, Weiss Susan R.51ORCID, Bonnet Damien41ORCID, Duval Xavier52535455, Pan-Hammarström Qiang56ORCID, Planas Anna M.5758ORCID, Meyts Isabelle59ORCID, Haerynck Filomeen60ORCID, Pujol Aurora6162ORCID, Sancho-Shimizu Vanessa6364ORCID, Dalgard Clifford L.6566ORCID, Bustamante Jacinta12367ORCID, Puel Anne123ORCID, Boisson-Dupuis Stéphanie123ORCID, Boisson Bertrand123ORCID, Maniatis Tom68ORCID, Zhang Qian123ORCID, Bastard Paul12369ORCID, Notarangelo Luigi28ORCID, Béziat Vivien123ORCID, Perez de Diego Rebeca7071ORCID, Rodriguez-Gallego Carlos7273, Su Helen C.2829ORCID, Lifton Richard P.2474, Jouanguy Emmanuelle123ORCID, Cobat Aurélie123ORCID, Alsina Laia10123775ORCID, Keles Sevgi76, Haddad Elie77ORCID, Abel Laurent123ORCID, Belot Alexandre2178ORCID, Quintana-Murci Lluis679ORCID, Rice Charles M.4ORCID, Silverman Robert H.5ORCID, Zhang Shen-Ying123ORCID, Casanova Jean-Laurent1238081ORCID, Alavoine Loubna, Behillil Sylvie, Burdet Charles, Charpentier Charlotte, Dechanet Aline, Descamps Diane, Duval Xavier, Ecobichon Jean-Luc, Enouf Vincent, Frezouls Wahiba, Houhou Nadhira, Kafif Ouifiya, Lehacaut Jonathan, Letrou Sophie, Lina Bruno, Lucet Jean-Christophe, Manchon Pauline, Nouroudine Mariama, Piquard Valentine, Quintin Caroline, Thy Michael, Tubiana Sarah, van der Werf Sylvie, Vignali Valérie, Visseaux Benoit, Yazdanpanah Yazdan, Chahine Abir, Waucquier Nawal, Migaud Maria-Claire, Deplanque Dominique, Djossou Félix, Mergeay-Fabre Mayka, Lucarelli Aude, Demar Magalie, Bruneau Léa, Gérardin Patrick, Maillot Adrien, Payet Christine, Laviolle Bruno, Laine Fabrice, Paris Christophe, Desille-Dugast Mireille, Fouchard Julie, Malvy Denis, Nguyen Duc, Pistone Thierry, Perreau Pauline, Gissot Valérie, Le Goas Carole, Montagne Samatha, Richard Lucie, Chirouze Catherine, Bouiller Kévin, Desmarets Maxime, Meunier Alexandre, Lefèvre Benjamin, Jeulin Hélène, Legrand Karine, Lomazzi Sandra, Tardy Bernard, Gagneux-Brunon Amandine, Bertholon Frédérique, Botelho-Nevers Elisabeth, Christelle Kouakam, Nicolas Leturque, Roufai Layidé, Amat Karine, Couffin-Cadiergues Sandrine, Espérou Hélène, Hendou Samia, Abel Laurent, Abolhassani Hassan, Aguilera-Albesa Sergio, Aiuti Alessandro, Akcan Ozge Metin, Akcay Nihal, Alkan Gulsum, Alkhater Suzan A., Allende Luis Miguel, Alper Yosunkaya, Amenzoui Naima, Anderson Mark S., Arkin Lisa, Aubart Melodie, Avramenko Iryna, Aydemir Şehnaz, Gayretli Aydin Zeynep Gökçe, Aytekin Caner, Aytekin Gökhan, Erol Aytekin Selma, Bando Silvia Yumi, Beland Kathie, Belkaya Serkan, Biggs Catherine M., Bilbao Aburto Agurtzane, Blanchard-Rohner Geraldine, Blázquez-Gamero Daniel, Bloomfield Marketa, Bogunovic Dusan, Bondarenko Anastasia, Borghesi Alessandro, Bousfiha Amed Aziz, Boyarchuk Oksana, Brodin Petter, Bryceson Yenan, Bucciol Giorgia, Calcaterra Valeria, Casari Giorgio, Cavalcanti Andre, Celik Jale Bengi, Chrousos George P., Colobran Roger, Condino-Neto Antonio, Conti Francesca, Cooper Megan, Coskuner Taner, Cyrus Cyril, D’Auria Enza, Delafontaine Selket, Drolet Beth A., Bursal Duramaz Burcu, El Zein Loubna, Elnagdy Marwa H., Emiroglu Melike, Erdeniz Emine Hafize, Fabi Marianna, Baris Feldman Hagit, Fellay Jacques, Fencl Filip, Filippatos Filippos, Freiss Julie, Fremuth Jiri, Gagro Alenka, Garcia-Solis Blanca, Vergine Gianluca, González-Montelongo Rafaela, Gul Yahya, Gülhan Belgin, Gultekin Sara Sebnem Kilic, Gut Marta, Halwani Rabih, Hammarström Lennart, Hatipoğlu Nevin, Heath James, Henrickson Sarah E., Hernandez-Brito Elisa, Hoffman Ilse, Hoste Levi, Hsieh Elena, Íñigo-Campos Antonio, Itan Yuval, Jabandziev Petr, Kandemir Bahar, Kanık-Yüksek Saliha, Kapakli Hasan, Karbuz Adem, Kasapcopur Ozgur, Kechiche Robin, Kendir Demirkol Yasemin, Kilic Omer, Hansen Stella Kim, Klocperk Adam, Lau Yu-Lung, Lebl Jan, Lorenzo-Salazar José M., Lucas Carrie L., Maglorius Majistor, Marque Laura, Novoa Medina Yeray, Montesdeoca Melián Abián, Mentis Alexios-Fotios A., Pato Michele T., Michos Athanasios, Milner Joshua D., Mogensen Trine H., Muñoz-Barrera Adrián, Nepesov Serdar, Farela Neves João, Ng Ashley, Ng Lisa F. P., Novelli Antonio, Novelli Giuseppe, Oz Fatma Nur, Ocejo-Viñals J. Gonzalo, Okada Satoshi, Orbak Zerrin, Kilic Ahmet Osman, Ouair Hind, Öz Şadiye Kübra Tüter, Özçelik Tayfun, Özkan Esra Akyüz, Parlakay Aslınur Özkaya, Pato Carlos N., Paz-Artal Estela, Pelham Simon, Pellier Isabelle, Philippot Quentin, Planas-Serra Laura, Plassart Samira, Pokorna Petra, Polat Meltem, Poli Cecilia, Prando Carolina, Renia Laurent, Rivière Jacques G., Rodríguez-Palmero Agustí, Roussel Lucie, Rubio-Rodriguez Luis A., Salifu Moro, Sasek Lumir, Sasia Laura, Scherbina Anna, Schmitt Erica, Sediva Anna, Sevketoglu Esra, Slaba Katerina, Slaby Ondrej, Sobh Ali, Solé-Violán Jordi, Soler-Palacin Pere, De Somer Lien, Sözeri Betül, Spaan András N., Stepanovskiy Yuriy, Tangye Stuart G., Tanir Gonul, Tatsi Elizabeth Barbara, Thorball Christian W., Hancerli Torun Selda, Turvey Stuart, Uddin Mohammed J., Uyar Emel, Valencia-Ramos Juan, Van Den Rym Ana Maria, Vatansev Hulya, Castillo de Vera Martín, Vermeulen François, Vinh Donald C., Volokha Alla, von Bernuth Horst, Wouters Carine, Yahşi Aysun, Yarar Volkan, Yesilbas Osman, Yıldız Mehmet, Zatz Mayana, Zawadzki Pawel, Zuccotti Gianvincenzo, Zhang Shen-Ying, Casanova Jean-Laurent, ,
Affiliation:
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.
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.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Multidisciplinary
Cited by
50 articles.
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