Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia
Author:
Zhang Qian123ORCID, Matuozzo Daniela23ORCID, Le Pen Jérémie4ORCID, Lee Danyel123ORCID, Moens Leen4ORCID, Asano Takaki1ORCID, Bohlen Jonathan23ORCID, Liu Zhiyong1ORCID, Moncada-Velez Marcela1ORCID, Kendir-Demirkol Yasemin1ORCID, Jing Huie5ORCID, Bizien Lucy23ORCID, Marchal Astrid23ORCID, Abolhassani Hassan67ORCID, Delafontaine Selket89ORCID, Bucciol Giorgia8ORCID, Abel Laurent, Abolhassani Hassan, Aiuti Alessandro, Akcan Ozge Metin, Al-Muhsen Saleh, Al-Mulla Fahd, Alkan Gulsum, Anderson Mark S., Andreakos Evangelos, Arias Andrés A., El Bakkouri Jalila, Baris Feldman Hagit, Belot Alexandre, Biggs Catherine M., Bogunovic Dusan, Bolze Alexandre, Bondarenko Anastasiia, Bousfiha Ahmed A., Bozdemir Sefika Elmas, Brodin Petter, Bryceson Yenan, Bustamante Carlos D., Butte Manish J., Casari Giorgio, Christodoulou John, Colobran Roger, Condino-Neto Antonio, Constantinescu Stefan N., Cooper Megan A., Dalgard Clifton L., Desai Murkesh, Drolet Beth A., El Baghdadi Jamila, Emiroglu Melike, Erdeniz Emine Hafize, Espinosa-Padilla Sara, Fellay Jacques, Flores Carlos, Franco José Luis, Froidure Antoine, Gregersen Peter K., Grimbacher Bodo, Gulhan Belgin, Haerynck Filomeen, Hagin David, Halwani Rabih, Hammarström Lennart, Heath James R., Henrickson Sarah E., Hsieh Elena W.Y., Husebye Eystein, Imai Kohsuke, Itan Yuval, Jabandziev Petr, Jarvis Erich D., Karamitros Timokratis, Karbuz Adem, Kisand Kai, Ku Cheng-Lung, Lau Yu-Lung, Ling Yun, Lucas Carrie L., Maniatis Tom, Mansouri Davood, Maródi László, Metin Ayse, Meyts Isabelle, Milner Joshua D., Mironska Kristina, Mogensen Trine H., Morio Tomohiro, Ng Lisa F.P., Notarangelo Luigi D., Novelli Antonio, Novelli Giuseppe, O'Farrelly Cliona, Okada Satoshi, Okamoto Keisuke, Tüter Öz Şadiye Kübra, Ozcelik Tayfun, Pan-Hammarström Qiang, Papadaki Maria, Pape Jean W., Parlakay Aslinur Ozkaya, Perez de Diego Rebeca, Perlin David S., Pesole Graziano, Planas Anna M., Pokorna Petra, Prando Carolina, Pujol Aurora, Quintana-Murci Lluis, Ramaswamy Sathishkumar, Renia Laurent, Resnick Igor, Rivière Jacques G., Rodríguez-Gallego Carlos, Sancho-Shimizu Vanessa, Sediva Anna, Seppänen Mikko R.J., Shahrooei Mohammed, Shcherbina Anna, Slaba Katerina, Slaby Ondrej, Snow Andrew L., Soler-Palacín Pere, De Somer Lien, Spaan András N., Tancevski Ivan, Tangye Stuart G., Abou Tayoun Ahmad, Thanos Dimitris, Turvey Stuart E., Uddin K M Furkan, Uddin Mohammed J., van de Beek Diederik, Vermeulen François, Vinh Donald C., von Bernuth Horst, Wauters Joost, Wouters Carine, Yahsi Aysun, Kanik Yuksek Saliha, Zatz Mayana, Zawadzki Pawel, Su Helen C., Casanova Jean-Laurent, Bayhan Gulsum Ical10ORCID, Keles Sevgi11ORCID, Kiykim Ayca12ORCID, Hancerli Selda13ORCID, Haerynck Filomeen14ORCID, Florkin Benoit15ORCID, Hatipoglu Nevin16ORCID, Ozcelik Tayfun17ORCID, Morelle Guillaume18ORCID, Zatz Mayana19ORCID, Ng Lisa F.P.20ORCID, Lye David Chien21222324ORCID, Young Barnaby Edward212324ORCID, Leo Yee-Sin21222324ORCID, Dalgard Clifton L.2526ORCID, Lifton Richard P.272829ORCID, Renia Laurent202330ORCID, Meyts Isabelle8ORCID, Jouanguy Emmanuelle123ORCID, Hammarström Lennart6ORCID, Pan-Hammarström Qiang6ORCID, Boisson Bertrand123ORCID, Bastard Paul12331ORCID, Su Helen C.5ORCID, Boisson-Dupuis Stéphanie123ORCID, Abel Laurent123ORCID, Rice Charles M.4ORCID, Zhang Shen-Ying123ORCID, Cobat Aurélie123ORCID, Casanova Jean-Laurent1233132ORCID,
Affiliation:
1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 1 2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France 2 3. University Paris Cité, Imagine Institute, Paris, France 3 4. Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 4 5. Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 6 6. Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden 7 7. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran 8 8. Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium 5 9. Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium 9 10. Yildirim Beyazit University, Ankara City Hospital, Ankara, Turkey 10 11. Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey 11 12. Istanbul University-Cerrahpasa, Pediatric Allergy and Immunology, Istanbul, Turkey 12 13. Department of Pediatrics (Infectious Diseases), Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey 13 14. Department of Pediatric Immunology and Pulmonology, Department of Internal Medicine and Pediatrics, Centre for Primary Immunodeficiency Ghent, PID Research Laboratory, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium 14 15. Department of Pediatrics, Hôpital de la Citadelle, Liége, Belgium 15 16. Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey 16 17. Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey 17 18. Department of General Pediatrics, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University of Paris Saclay, Le Kremlin-Bicêtre, France 18 19. Biosciences Institute, University of São Paulo, São Paulo, Brazil 19 20. A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 20 21. National Centre for Infectious Diseases, Singapore, Singapore 21 22. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore 22 23. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 23 24. Tan Tock Seng Hospital, Singapore, Singapore 24 25. The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD 25 26. Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 26 27. Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY 27 28. Department of Genetics, Yale University School of Medicine, New Haven, CT 28 29. Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 29 30. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore 30 31. Department of Pediatrics, Necker Hospital for Sick Children, Paris, France 31 32. Howard Hughes Medical Institute, New York, NY 32
Abstract
Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5–13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10−11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.
Funder
Howard Hughes Medical Institute Rockefeller University St. Giles Foundation National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Award Fast Grant from Emergent Ventures Mercatus Center at George Mason University Yale Center for Mendelian Genomics GSP Coordinating Center National Human Genome Research Institute Yale High Performance Computing Center Fisher Center for Alzheimer’s Research Foundation JPB Foundation Meyer Foundation French National Research Agency Investments for the Future Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence Foundation for Medical Research Agence Nationale de la Recherche Agence Nationale de Recherches sur le Sida et les Hépatites Virales European Union’s Horizon 2020 Square Foundation Grandir - Fonds de solidarité pour l’enfance, Fondation du Souffle SCOR Corporate Foundation for Science Ministry of Higher Education, Research, and Innovation Institut National de la Santé et de la Recherche Médicale University of Paris Laboratory of Virology and Infectious Disease George Mason University G. Harold and Leila Y. Mathers Charitable Foundation Bawd Foundation Francois Wallace Monahan Postdoctoral Fellowship European Molecular Biology Organization Imagine Institute Fondation Bettencourt-Schueller Intramural Research Program National Institute of Allergy and Infectious Diseases Regione Lazio Research Group Projects 2020 Research Foundation—Flanders CSL Behring KU Leuven Vlaams Instituut voor Biotechnologie Fonds Wetenschappelijk Onderzoek Jeffrey Modell Foundation European Research Council National Medical Research Council A*STAR COVID-19 Research funding Instituto de Salud Carlos III Spanish Ministry of Science and Innovation Albert Ellis Institute Cabildo Insular de Tenerife
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy
Cited by
61 articles.
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