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

Lee, D.; Le Pen, J.; Yatim, A.; Dong, B.; Aquino, Y.; Ogishi, M.; Pescarmona, R.; Talouarn, E.; Rinchai, D.; Zhang, P.; Perret, M.; Liu, Z.; Jordan, I.; Elmas Bozdemir, S.; Bayhan, G.I.; Beaufils, C.; Bizien, L.; Bisiaux, A.; Lei, W.; Hasan, M.; Chen, J.; Gaughan, C.; Asthana, A.; Libri, V.; Luna, J.M.; Jaffré, F.; Hoffmann, H.-.; Michailidis, E.; Moreews, M.; Seeleuthner, Y.; Bilguvar, K.; Mane, S.; Flores, C.; Zhang, Y.; Arias, A.A.; Bailey, R.; Schlüter, A.; Milisavljevic, B.; Bigio, B.; Le Voyer, T.; Materna, M.; Gervais, A.; Moncada-Velez, M.; Pala, F.; Lazarov, T.; Levy, R.; Neehus, A.; Rosain, J.; Peel, J.; Chan, Y.; Morin, M.; Pino-Ramirez, R.M.; Belkaya, S.; Lorenzo, L.; Anton, J.; Delafontaine, S.; Toubiana, J.; Bajolle, F.; Fumadó, V.; Dediego, M.L.; Fidouh, N.; Rozenberg, F.; Pérez-Tur, J.; Chen, S.; Evans, T.; Geissmann, F.; Lebon, P.; Weiss, S.R.; Bonnet, D.; Duval, X.; Null, N.; Null, N.; Pan-Hammarström, Q.; Planas, A.M.; Meyts, I.; Haerynck, F.; Pujol, A.; Sancho-Shimizu, V.; Dalgard, C.L.; Bustamante, J.; Puel, A.; Boisson-Dupuis, S.; Boisson, B.; Maniatis, T.; Zhang, Q.; Bastard, P.; Notarangelo, L.; Béziat, V.; Perez De Diego, R.; Rodriguez-Gallego, C.; Helen C., S.; Lifton, R.P.; Jouanguy, E.; Cobat, A.; Alsina, L.; Keles, S.; Haddad, E.; Abel, L.; Belot, A.; Quintana-Murci, L.; Rice, C.M.; Silverman, R.H.; Zhang, S.; Casanova, J.; Alavoine, L.; Behillil, S.; Burdet, C.; Charpentier, C.; Dechanet, A.; Descamps, D.; Duval, X.; Ecobichon, J.; Enouf, V.; Frezouls, W.; Houhou, N.; Kafif, O.; Lehacaut, J.; Letrou, S.; Lina, B.; Lucet, J.; Manchon, P.; Nouroudine, M.; Piquard, V.; Quintin, C.; Thy, M.; Tubiana, S.; Van Der Werf, S.; Vignali, V.; Visseaux, B.; Yazdanpanah, Y.; Chahine, A.; Waucquier, N.; Migaud, M.; Deplanque, D.; Djossou, F.; Mergeay-Fabre, M.; Lucarelli, A.; Demar, M.; Bruneau, L.; Gérardin, P.; Maillot, A.; Payet, C.; Laviolle, B.; Laine, F.; Paris, C.; Desille-Dugast, M.; Fouchard, J.; Malvy, D.; Nguyen, D.; Pistone, T.; Perreau, P.; Gissot, V.; Le Goas, C.; Montagne, S.; Richard, L.; Chirouze, C.; Bouiller, K.; Desmarets, M.; Meunier, A.; Lefèvre, B.; Jeulin, H.; Legrand, K.; Lomazzi, S.; Tardy, B.; Gagneux-Brunon, A.; Bertholon, F.; Botelho-Nevers, E.; Christelle, K.; Nicolas, L.; Roufai, L.; Amat, K.; Couffin-Cadiergues, S.; Espérou, H.; Hendou, S.; Abel, L.; Abolhassani, H.; Aguilera-Albesa, S.; Aiuti, A.; Akcan, O.M.; Akcay, N.; Alkan, G.; Alkhater, S.A.; Allende, L.M.; Alper, Y.; Amenzoui, N.; Anderson, M.S.; Arkin, L.; Aubart, M.; Avramenko, I.; Aydemir, Ş.; Gayretli Aydin, Z.G.; Aytekin, C.; Aytekin, G.; Erol Aytekin, S.; Bando, S.Y.; Beland, K.; Belkaya, S.; Biggs, C.M.; Bilbao Aburto, A.; Blanchard-Rohner, G.; Blázquez-Gamero, D.; Bloomfield, M.; Bogunovic, D.; Bondarenko, A.; Borghesi, A.; Bousfiha, A.A.; Boyarchuk, O.; Brodin, P.; Bryceson, Y.; Bucciol, G.; Calcaterra, V.; Casari, G.; Cavalcanti, A.; Celik, J.B.; Chrousos, G.P.; Colobran, R.; Condino-Neto, A.; Conti, F.; Cooper, M.; Coskuner, T.; Cyrus, C.; D'Auria, E.; Delafontaine, S.; Drolet, B.A.; Bursal Duramaz, B.; El Zein, L.; Elnagdy, M.H.; Emiroglu, M.; Erdeniz, E.H.; Fabi, M.; Baris Feldman, H.; Fellay, J.; Fencl, F.; Filippatos, F.; Freiss, J.; Fremuth, J.; Gagro, A.; Garcia-Solis, B.; Vergine, G.; González-Montelongo, R.; Gul, Y.; Gülhan, B.; Gultekin, S.S.K.; Gut, M.; Halwani, R.; Hammarström, L.; Hatipoğlu, N.; Heath, J.; Henrickson, S.E.; Hernandez-Brito, E.; Hoffman, I.; Hoste, L.; Hsieh, E.; Íñigo-Campos, A.; Itan, Y.; Jabandziev, P.; Kandemir, B.; Kanık-Yüksek, S.; Kapakli, H.; Karbuz, A.; Kasapcopur, O.; Kechiche, R.; Kendir Demirkol, Y.; Kilic, O.; Hansen, S.K.; Klocperk, A.; Lau, Y.; Lebl, J.; Lorenzo-Salazar, J.M.; Lucas, C.L.; Maglorius, M.; Marque, L.; Novoa Medina, Y.; Montesdeoca Melián, A.; Mentis, A.A.; Pato, M.T.; Michos, A.; Milner, J.D.; Mogensen, T.H.; Muñoz-Barrera, A.; Nepesov, S.; Farela Neves, J.; Ashley, N.; Lisa F. P., N.; Novelli, A.; Novelli, G.; Fatma Nur, O.; Ocejo-Viñals, J.G.; Okada, S.; Orbak, Z.; Kilic, A.O.; Ouair, H.; Şadiye Kübra Tüter, Ö.; Özçelik, T.; Özkan, E.A.; Parlakay, A.Ö.; Pato, C.N.; Paz-Artal, E.; Pelham, S.; Pellier, I.; Philippot, Q.; Planas-Serra, L.; Plassart, S.; Pokorna, P.; Polat, M.; Poli, C.; Prando, C.; Renia, L.; Rivière, J.G.; Rodríguez-Palmero, A.; Roussel, L.; Rubio-Rodriguez, L.A.; Salifu, M.; Sasek, L.; Sasia, L.; Scherbina, A.; Schmitt, E.; Sediva, A.; Sevketoglu, E.; Slaba, K.; Slaby, O.; Sobh, A.; Solé-Violán, J.; Soler-Palacin, P.; De Somer, L.; Sözeri, B.; Spaan, A.N.; Stepanovskiy, Y.; Tangye, S.G.; Tanir, G.; Tatsi, E.B.; Thorball, C.W.; Hancerli Torun, S.; Turvey, S.; Uddin, M.J.; Uyar, E.; Valencia-Ramos, J.; Van Den Rym, A.M.; Vatansev, H.; Castillo De Vera, M.; Vermeulen, F.; Vinh, D.C.; Volokha, A.; Von Bernuth, H.; Wouters, C.; Yahşi, A.; Yarar, V.; Yesilbas, O.; Yıldız, M.; Zatz, M.; Zawadzki, P.; Zuccotti, G.; Zhang, S.; Casanova, J.

doi:10.1126/science.abo3627

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.

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children / D. Lee, J. Le Pen, A. Yatim, B. Dong, Y. Aquino, M. Ogishi, R. Pescarmona, E. Talouarn, D. Rinchai, P. Zhang, M. Perret, Z. Liu, I. Jordan, S. Elmas Bozdemir, G.I. Bayhan, C. Beaufils, L. Bizien, A. Bisiaux, W. Lei, M. Hasan, J. Chen, C. Gaughan, A. Asthana, V. Libri, J.M. Luna, F. Jaffré, H.-. Hoffmann, E. Michailidis, M. Moreews, Y. Seeleuthner, K. Bilguvar, S. Mane, C. Flores, Y. Zhang, A.A. Arias, R. Bailey, A. Schlüter, B. Milisavljevic, B. Bigio, T. Le Voyer, M. Materna, A. Gervais, M. Moncada-Velez, F. Pala, T. Lazarov, R. Levy, A. Neehus, J. Rosain, J. Peel, Y. Chan, M. Morin, R.M. Pino-Ramirez, S. Belkaya, L. Lorenzo, J. Anton, S. Delafontaine, J. Toubiana, F. Bajolle, V. Fumadó, M.L. Dediego, N. Fidouh, F. Rozenberg, J. Pérez-Tur, S. Chen, T. Evans, F. Geissmann, P. Lebon, S.R. Weiss, D. Bonnet, X. Duval, N. Null, N. Null, Q. Pan-Hammarström, A.M. Planas, I. Meyts, F. Haerynck, A. Pujol, V. Sancho-Shimizu, C.L. Dalgard, J. Bustamante, A. Puel, S. Boisson-Dupuis, B. Boisson, T. Maniatis, Q. Zhang, P. Bastard, L. Notarangelo, V. Béziat, R. Perez de Diego, C. Rodriguez-Gallego, H.C. Su, R.P. Lifton, E. Jouanguy, A. Cobat, L. Alsina, S. Keles, E. Haddad, L. Abel, A. Belot, L. Quintana-Murci, C.M. Rice, R.H. Silverman, S. Zhang, J. Casanova, L. Alavoine, S. Behillil, C. Burdet, C. Charpentier, A. Dechanet, D. Descamps, X. Duval, J. Ecobichon, V. Enouf, W. Frezouls, N. Houhou, O. Kafif, J. Lehacaut, S. Letrou, B. Lina, J. Lucet, P. Manchon, M. Nouroudine, V. Piquard, C. Quintin, M. Thy, S. Tubiana, S. van der Werf, V. Vignali, B. Visseaux, Y. Yazdanpanah, A. Chahine, N. Waucquier, M. Migaud, D. Deplanque, F. Djossou, M. Mergeay-Fabre, A. Lucarelli, M. Demar, L. Bruneau, P. Gérardin, A. Maillot, C. Payet, B. Laviolle, F. Laine, C. Paris, M. Desille-Dugast, J. Fouchard, D. Malvy, D. Nguyen, T. Pistone, P. Perreau, V. Gissot, C. Le Goas, S. Montagne, L. Richard, C. Chirouze, K. Bouiller, M. Desmarets, A. Meunier, B. Lefèvre, H. Jeulin, K. Legrand, S. Lomazzi, B. Tardy, A. Gagneux-Brunon, F. Bertholon, E. Botelho-Nevers, K. Christelle, L. Nicolas, L. Roufai, K. Amat, S. Couffin-Cadiergues, H. Espérou, S. Hendou, L. Abel, H. Abolhassani, S. Aguilera-Albesa, A. Aiuti, O.M. Akcan, N. Akcay, G. Alkan, S.A. Alkhater, L.M. Allende, Y. Alper, N. Amenzoui, M.S. Anderson, L. Arkin, M. Aubart, I. Avramenko, Ş. Aydemir, Z.G. Gayretli Aydin, C. Aytekin, G. Aytekin, S. Erol Aytekin, S.Y. Bando, K. Beland, S. Belkaya, C.M. Biggs, A. Bilbao Aburto, G. Blanchard-Rohner, D. Blázquez-Gamero, M. Bloomfield, D. Bogunovic, A. Bondarenko, A. Borghesi, A.A. Bousfiha, O. Boyarchuk, P. Brodin, Y. Bryceson, G. Bucciol, V. Calcaterra, G. Casari, A. Cavalcanti, J.B. Celik, G.P. Chrousos, R. Colobran, A. Condino-Neto, F. Conti, M. Cooper, T. Coskuner, C. Cyrus, E. D'Auria, S. Delafontaine, B.A. Drolet, B. Bursal Duramaz, L. El Zein, M.H. Elnagdy, M. Emiroglu, E.H. Erdeniz, M. Fabi, H. Baris Feldman, J. Fellay, F. Fencl, F. Filippatos, J. Freiss, J. Fremuth, A. Gagro, B. Garcia-Solis, G. Vergine, R. González-Montelongo, Y. Gul, B. Gülhan, S.S.K. Gultekin, M. Gut, R. Halwani, L. Hammarström, N. Hatipoğlu, J. Heath, S.E. Henrickson, E. Hernandez-Brito, I. Hoffman, L. Hoste, E. Hsieh, A. Íñigo-Campos, Y. Itan, P. Jabandziev, B. Kandemir, S. Kanık-Yüksek, H. Kapakli, A. Karbuz, O. Kasapcopur, R. Kechiche, Y. Kendir Demirkol, O. Kilic, S.K. Hansen, A. Klocperk, Y. Lau, J. Lebl, J.M. Lorenzo-Salazar, C.L. Lucas, M. Maglorius, L. Marque, Y. Novoa Medina, A. Montesdeoca Melián, A.A. Mentis, M.T. Pato, A. Michos, J.D. Milner, T.H. Mogensen, A. Muñoz-Barrera, S. Nepesov, J. Farela Neves, A. Ng, L.F.P. Ng, A. Novelli, G. Novelli, F.N. Oz, J.G. Ocejo-Viñals, S. Okada, Z. Orbak, A.O. Kilic, H. Ouair, Ş.K.T. Öz, T. Özçelik, E.A. Özkan, A.Ö. Parlakay, C.N. Pato, E. Paz-Artal, S. Pelham, I. Pellier, Q. Philippot, L. Planas-Serra, S. Plassart, P. Pokorna, M. Polat, C. Poli, C. Prando, L. Renia, J.G. Rivière, A. Rodríguez-Palmero, L. Roussel, L.A. Rubio-Rodriguez, M. Salifu, L. Sasek, L. Sasia, A. Scherbina, E. Schmitt, A. Sediva, E. Sevketoglu, K. Slaba, O. Slaby, A. Sobh, J. Solé-Violán, P. Soler-Palacin, L. De Somer, B. Sözeri, A.N. Spaan, Y. Stepanovskiy, S.G. Tangye, G. Tanir, E.B. Tatsi, C.W. Thorball, S. Hancerli Torun, S. Turvey, M.J. Uddin, E. Uyar, J. Valencia-Ramos, A.M. Van Den Rym, H. Vatansev, M. Castillo de Vera, F. Vermeulen, D.C. Vinh, A. Volokha, H. von Bernuth, C. Wouters, A. Yahşi, V. Yarar, O. Yesilbas, M. Yıldız, M. Zatz, P. Zawadzki, G. Zuccotti, S. Zhang, J. Casanova. - In: SCIENCE. - ISSN 0036-8075. - 379:6632(2023), pp. eabo3627.1-eabo3627.21. [10.1126/science.abo3627]

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

Lee, Danyel;Le Pen, Jérémie;Yatim, Ahmad;Dong, Beihua;Aquino, Yann;Ogishi, Masato;Pescarmona, Rémi;Talouarn, Estelle;Rinchai, Darawan;Zhang, Peng;Perret, Magali;Liu, Zhiyong;Jordan, Iolanda;Elmas Bozdemir, Sefika;Bayhan, Gulsum Iclal;Beaufils, Camille;Bizien, Lucy;Bisiaux, Aurelie;Lei, Weite;Hasan, Milena;Chen, Jie;Gaughan, Christina;Asthana, Abhishek;Libri, Valentina;Luna, Joseph M.;Jaffré, Fabrice;Hoffmann, H. -Heinrich;Michailidis, Eleftherios;Moreews, Marion;Seeleuthner, Yoann;Bilguvar, Kaya;Mane, Shrikant;Flores, Carlos;Zhang, Yu;Arias, Andrés A.;Bailey, Rasheed;Schlüter, Agatha;Milisavljevic, Baptiste;Bigio, Benedetta;Le Voyer, Tom;Materna, Marie;Gervais, Adrian;Moncada-Velez, Marcela;Pala, Francesca;Lazarov, Tomi;Levy, Romain;Neehus, Anna-Lena;Rosain, Jérémie;Peel, Jessica;Chan, Yi-Hao;Morin, Marie-Paule;Pino-Ramirez, Rosa Maria;Belkaya, Serkan;Lorenzo, Lazaro;Anton, Jordi;Delafontaine, Selket;Toubiana, Julie;Bajolle, Fanny;Fumadó, Victoria;DeDiego, Marta L.;Fidouh, Nadhira;Rozenberg, Flore;Pérez-Tur, Jordi;Chen, Shuibing;Evans, Todd;Geissmann, Frédéric;Lebon, Pierre;Weiss, Susan R.;Bonnet, Damien;Duval, Xavier;null, null;null, null;Pan-Hammarström, Qiang;Planas, Anna M.;Meyts, Isabelle;Haerynck, Filomeen;Pujol, Aurora;Sancho-Shimizu, Vanessa;Dalgard, Clifford L.;Bustamante, Jacinta;Puel, Anne;Boisson-Dupuis, Stéphanie;Boisson, Bertrand;Maniatis, Tom;Zhang, Qian;Bastard, Paul;Notarangelo, Luigi;Béziat, Vivien;Perez de Diego, Rebeca;Rodriguez-Gallego, Carlos;Su, Helen C.;Lifton, Richard P.;Jouanguy, Emmanuelle;Cobat, Aurélie;Alsina, Laia;Keles, Sevgi;Haddad, Elie;Abel, Laurent;Belot, Alexandre;Quintana-Murci, Lluis;Rice, Charles M.;Silverman, Robert H.;Zhang, Shen-Ying;Casanova, Jean-Laurent;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;E. D'Auria;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;G. Zuccotti;Zhang, Shen-Ying;Casanova, Jean-Laurent

2023

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.

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				Settore MEDS-20/A - Pediatria generale e specialistica
			
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				2023
			
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				SCIENCE
			
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				https://dx.doi.org/10.1126/science.abo3627
			
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