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

Authors: 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 Jordán, Şefika Elmas Bozdemir, Gülsüm İclal Bayhan, Camille Beaufils, Lucy Bizien, Aurélie Bisiaux, Wei‐Te Lei, Milena Hasan, Jie Chen, Christina Gaughan, Abhishek Asthana, Valentina Libri, Joseph M. Luna, Fabrice Jaffré, Hans-Heinrich Hoffmann, Eleftherios Michailidis, Marion Moreews, Yoann Seeleuthner, Kaya Bilgüvar, 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‐Vélez, Francesca Pala, Tomi Lazarov, Romain Lévy, Anna‐Lena Neehus, Jérémie Rosain, Jessica N. Peel, Yi‐Hao Chan, Marie‐Paule Morin, Rosa Pino, Serkan Belkaya, Lazaro Lorenzo, Jordi Antón, Selket Delafontaine, Julie Toubiana, Fanny Bajolle, Victòria 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, CoV-Contact Cohort§, COVID Human Genetic Effort¶, 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 D. Notarangelo, Vivien Béziat, Rebeca Pérez de Diego, Carlos Rodríguez‐Gallego, Helen C. Su, Richard P. Lifton, Emmanuelle Jouanguy, Aurélie Cobat, Laia Alsina, Sevgi Keleş, Élie Haddad, Laurent Abel, Alexandre Bélot, Lluís Quintana‐Murci, Charles M. Rice, Robert H. Silverman, Shen-Ying Zhang, Jean-Laurent Casanova, Loubna Alavoine, Sylvie Behillil, Charles Burdet, Charlotte Charpentier, Aline Dechanet, Diane Descamps, Xavier Duval, Jean-Luc Ecobichon, Vincent Enouf, Wahiba Frezouls, Nadhira Houhou, Ouifiya Kafif, Jonathan Lehacaut, Sophie Letrou, Bruno Lina, Jean‐Christophe Lucet, Pauline Manchon, Mariama Nouroudine, Valentine Piquard, Caroline Quintin, Michaël Thy, Sarah Tubiana, Sylvie van der Werf, Valérie Vignali, Benoît Visseaux, Yazdan Yazdanpanah, Abir Chahine, Nawal Waucquier, Maria-Claire Migaud, Dominique Deplanque, F. Djossou, Mayka Mergeay-Fabre, Aude Lucarelli, Magalie Demar, Léa Bruneau, Patrick Gérardin, Adrien Maillot, Christine Payet, Bruno Laviolle, Fabrice Laine, Christophe Paris, Mireille Desille‐Dugast, Julie Fouchard, Denis Malvy, Duc Hai Nguyen, Thierry Pistone, Pauline Perreau, Valérie Gissot, Carole L. E. Goas, Samatha Montagne, Lucie Richard, Catherine Chirouze, Kévin Bouiller, Maxime Desmarets, Alexandre Meunier, Benjamin Lefèvre, Hélène Jeulin, Karine Legrand, Sandra Lomazzi, Bernard Tardy, Amandine Gagneux-Brunon, Frédérique Bertholon, Élisabeth Botelho-Nevers, Kouakam Christelle, Leturque Nicolas, Layidé Roufai, Karine Amat, Sandrine Couffin-Cadièrgues, Hélène Espérou, Samia Hendou, Laurent Abel, Hassan Abolhassani, Sergio Aguilera, Alessandro Aiuti, Özge Metin Akcan, Nihal Akçay, Gülsüm Alkan, Suzan A. AlKhater, Luís M. Allende, Alper Yosunkaya, N. Amenzoui, Mark Anderson, Lisa M. Arkin, Mélodie Aubart, Iryna Avramenko, Şehnaz Aydemir, Zeynep Gökçe Gayretli Aydın, Caner Aytekin, Gökhan Aytekіn, Selma Erol Aytekin, Sílvia Yumi Bando, Kathie Béland, Serkan Belkaya, Catherine M. Biggs, Agurtzane Bilbao Aburto, Géraldine Blanchard‐Rohner, Daniel Blázquez‐Gamero, Markéta Bloomfield, Dusan Bogunovic, Anastasia Bondarenko, A. Borghesi, Amed Aziz Bousfiha, Oksana Boyarchuk, Petter Brodin, Yenan T. Bryceson, Giorgia Bucciol, Valeria Calcaterra, Giorgio Casari, André Cavalcanti, Jale Bengi Çelik, George P. Chrousos, Roger Colobrán, Antônio Condino‐Neto, Francesca Conti, Megan A. Cooper, Taner Çoşkuner, Cyril Cyrus, Enza D’Auria, Selket Delafontaine, Beth A. Drolet, Burcu Bursal Duramaz, Loubna El Zein, Marwa H. Elnagdy, Melike Emiroğlu, Emine Hafize Erdeniz, Marianna Fabi, Hagit Baris Feldman, Jacques Fellay, Filip Fencl, Filippos Filippatos, Julie Freiss, Jiří Fremuth, Alenka Gagro, Blanca García‐Solis, Gianluca Vergine, Rafaela González‐Montelongo, Yahya Gül, Belgi̇n Gülhan, Sara Sebnem Kilic Gultekin, Marta Gut, Rabih Halwani, Lennart Hammarström, Nevin Hatipoğlu, James R. Heath, Sarah E. Henrickson, Elisa Hernández-Brito, Ilse Hoffman, Levi Hoste, Elena W.Y. Hsieh, Antonio Íñigo-Campos, Yuval Itan, Petr Jabandžiev, Bahar Kandemir, Saliha Kanık Yüksek, Hasan Kapaklı, Adem Karbuz, Özgür Kasapçopur, Robin Kechiche, Yasemin Kendir Demirkol, Ömer Kılıç, Stella Kim Hansen, Adam Klocperk, YL Lau, Jan Lebl, José M. Lorenzo-Salazar, C. Lucas, Majistor Maglorius, Laura Marque, Yeray Nóvoa Medina, Abián Montesdeoca Melián, Alexios‐Fotios A. Mentis, Michele T. Pato, Athanasios Michos, Joshua D. Milner, Trine H. Mogensen, Adrián Muñoz‐Barrera, Serdar Nepesov, João Farela Neves, Ashley Ng, Lisa F. P. Ng, Antonio Novelli, Giuseppe Novelli, Fatma Nur Öz, J. Gonzalo Ocejo‐Viñals, Satoshi Okada, Zerrin Orbak, Ahmet Osman Kılıç, Hind Ouair, Şadiye Kübra Tüter Öz, Tayfun Özçelık, Esra Akyüz Özkan, Aslınur Özkaya Parlakay, Carlos N. Pato, Estela Paz‐Artal, Simon J. Pelham, Isabelle Pellier, Quentin Philippot, Laura Planas‐Serra, Samira Plassart, Petra Pokorná, Meltem Polat, Cecilia Poli, Carolina Prando, Laurent Rénia, Jacques G. Rivière, Agustí Rodríguez‐Palmero, Lucie Roussel, Luis A. Rubio‐Rodríguez, Moro O. Salifu, Lumír Šašek, Laura Sasia, Anna Scherbina, Erica G. Schmitt, Anna Šedivá, Esra Şevketoğlu, Kateřina Slabá, Ondřej Slabý, Ali Sobh, Jordi Solé‐Violán, Pere Soler‐Palacín, Lien De Somer, Betül Sözeri, András N. Spaan, Yuriy Stepanovskiy, Stuart G. Tangye, Gönül Tanır, Elizabeth‐Barbara Tatsi, Christian W. Thorball, Selda Hançerlı Törün, Stuart E. Turvey, Mohammed Uddin, Emel Uyar, Juan Valencia-Ramos, Ana Maria Van Den Rym, Hülya Vatansev, Martín Castillo de Vera, F. Vermeulen, Donald C. Vinh, Алла Волоха, Horst von Bernuth, Carine Wouters, Aysun Yahşi, Volkan Yarar, Osman Yeşilbaş, Mehmet Yıldız, Mayana Zatz, Paweł Zawadzki, Gianvincenzo Zuccotti, Shen-Ying Zhang, Jean-Laurent Casanova - Science 2022 cited by 167

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.