Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia-Reference-Cited by-同舟云学术

Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

Published:2023-03-03 Issue:5 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
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Author:

García-García Ana¹²³^ORCID,Pérez de Diego Rebeca⁴^ORCID,Flores Carlos⁵⁶⁷⁸^ORCID,Rinchai Darawan⁹^ORCID,Solé-Violán Jordi⁷⁸¹⁰^ORCID,Deyà-Martínez Àngela¹²³^ORCID,García-Solis Blanca⁴^ORCID,Lorenzo-Salazar José M.⁵^ORCID,Hernández-Brito Elisa¹¹^ORCID,Lanz Anna-Lisa¹²^ORCID,Moens Leen¹³^ORCID,Bucciol Giorgia¹³¹⁴^ORCID,Almuqamam Mohamed¹⁵^ORCID,Domachowske Joseph B.¹⁶^ORCID,Colino Elena¹⁷^ORCID,Santos-Perez Juan Luis¹⁸^ORCID,Marco Francisco M.¹⁹²⁰^ORCID,Pignata Claudio²¹^ORCID,Bousfiha Aziz²²²³^ORCID,Turvey Stuart E.²⁴^ORCID,Bauer Stefanie²⁵^ORCID,Haerynck Filomeen²⁶²⁷^ORCID,Ocejo-Vinyals Javier Gonzalo²⁸^ORCID,Lendinez Francisco²⁹^ORCID,Prader Seraina³⁰^ORCID,Naumann-Bartsch Nora²⁵^ORCID,Pachlopnik Schmid Jana³⁰^ORCID,Biggs Catherine M.²⁴^ORCID,Hildebrand Kyla²⁴^ORCID,Dreesman Alexandra³¹^ORCID,Cárdenes Miguel Ángel³²^ORCID,Ailal Fatima²²²³^ORCID,Benhsaien Ibtihal²²²³^ORCID,Giardino Giuliana²¹^ORCID,Molina-Fuentes Agueda³³^ORCID,Fortuny Claudia²³⁴³⁵³⁶^ORCID,Madhavarapu Swetha¹⁵^ORCID,Conway Daniel H.¹⁵^ORCID,Prando Carolina³⁷^ORCID,Schidlowski Laire³⁷^ORCID,Martínez de Saavedra Álvarez María Teresa¹¹^ORCID,Alfaro Rafael¹¹^ORCID,Rodríguez de Castro Felipe³⁸³⁹^ORCID,Kindle Gerhard,Mahlaoui Nizar,Seidel Markus G.,Vassilios Lougaris,Seppänen Mikko R.J.,Abel Laurent,Aiuti Alessandro,Al-Muhsen Saleh,Al-Mulla Fahd,Anderson Mark S.,Andreakos Evangelos,Arias Andrés A.,Baris Feldman Hagit,Belot Alexandre,Biggs Catherine M.,Bogunovic Dusan,Bolze Alexandre,Bondarenko Anastasiia,Bousfiha Ahmed A.,Brodin Petter,Bryceson Yenan,Bustamante Carlos D.,Butte Manish J.,Casari Giorgio,Christodoulou John,Condino-Neto Antonio,Constantinescu Stefan N.,Cooper Megan A.,Dalgard Clifton L.,Desai Murkesh,Drolet Beth A.,El Baghdadi Jamila,Espinosa-Padilla Sara,Fellay Jacques,Flores Carlos,Franco José Luis,Froidure Antoine,Gregersen Peter K.,Grimbacher Bodo,Haerynck Filomeen,Hagin David,Halwani Rabih,Hammarström Lennart,Heath James R.,Henrickson Sarah E.,Hsieh Elena W.Y.,Husebye Eystein,Imai Kohsuke,Itan Yuval,Jarvis Erich D.,Karamitros Timokratis,Kisand Kai,Ku Cheng-Lung,Lau Yu-Lung,Ling Yun,Lucas Carrie L.,Maniatis Tom,Mansouri Davood,Maródi László,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,Ozcelik Tayfun,Pan-Hammarström Qiang,Pape Jean W.,Perez de Diego Rebecca,Perlin David S.,Pesole Graziano,Planas Anna M.,Prando Carolina,Pujol Aurora,Quintana-Murci Lluis,Ramaswamy Sathishkumar,Renia Laurent,Resnick Igor,Rodríguez-Gallego Carlos,Sancho-Shimizu Vanessa,Sediva Anna,Seppänan Mikko R.J.,Shahrooei Mohammed,Shcherbina Anna,Slaby Ondrej,Snow Andrew L.,Soler-Palacín Pere,Spaan András N.,Tancevski Ivan,Tangye Stuart G.,Tayoun Ahmad Abou,Turvey Stuart E.,Uddin K M Furkan,Uddin Mohammed J.,van de Beek Diederik,Vinh Donald C.,von Bernuth Horst,Wauters Joost,Zatz Mayana,Zawadzki Pawel,Su Helen C.,Casanova Jean-Laurent,Meyts Isabelle¹³¹⁴^ORCID,Hauck Fabian¹²^ORCID,Puel Anne⁹⁴⁰⁴¹^ORCID,Bastard Paul⁹⁴⁰⁴¹⁴²^ORCID,Boisson Bertrand⁹⁴⁰⁴¹^ORCID,Jouanguy Emmanuelle⁹⁴⁰⁴¹^ORCID,Abel Laurent⁹⁴⁰⁴¹^ORCID,Cobat Aurélie⁴⁰⁴¹^ORCID,Zhang Qian⁹⁴⁰⁴¹^ORCID,Casanova Jean-Laurent⁹⁴⁰⁴¹⁴³⁴⁴^ORCID,Alsina Laia¹²³³⁶^ORCID,Rodríguez-Gallego Carlos⁸¹¹³⁸^ORCID, ,

Affiliation:

1. Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona 1 , Barcelona, Spain

2. Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona 2 , Barcelona, Spain

3. Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona 3 , Barcelona, Spain

4. Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital 4 , Madrid, Spain

5. Genomics Division, Instituto Tecnológico y de Energías Renovables 5 , Santa Cruz de Tenerife, Spain

6. Research Unit, Hospital Universitario N.S. de Candelaria 6 , Santa Cruz de Tenerife, Spain

7. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III 7 , Madrid, Spain

8. Dept. of Clinical Sciences, University Fernando Pessoa Canarias 8 , Las Palmas de Gran Canaria, Spain

9. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University 9 , New York, NY, USA

10. Dept. of Intensive Care Medicine, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System 10 , Las Palmas de Gran Canaria, Spain

11. Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System 11 , Las Palmas de Gran Canaria, Spain

12. Dept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München 12 , Munich, Germany

13. Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven 13 , Leuven, Belgium

14. Dept. of Pediatrics, Childhood Immunology, UZ Leuven 14 , Leuven, Belgium

15. Dept. of Pediatrics, Drexel University College of Medicine, St Christopher’s Hospital for Children 15 , Philadelphia, PA, USA

16. Dept. of Pediatrics, SUNY Upstate Medical University 16 , Syracuse, NY, USA

17. Unidad de Enfermedades Infecciosas, Complejo Hospitalario Universitario Insular-Materno Infantil 17 , Las Palmas de Gran Canaria, Spain

18. Unidad de Gestión Clínica de Pediatría y Cirugía Pediátrica, Hospital Virgen de las Nieves-IBS 18 , Granada, Spain

19. Dept. of Immunology, Alicante University General Hospital Doctor Balmis 19 , Alicante, Spain

20. Alicante Institute for Health and Biomedical Research 20 , Alicante, Spain

21. Dept. of Translational Medical Sciences, Section of Pediatrics, Federico II University 21 , Naples, Italy

22. Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital 22 , Casablanca, Morocco

23. Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University 23 , Casablanca, Morocco

24. Dept. of Paediatrics, BC Children’s Hospital, University of British Columbia 24 , Vancouver, Canada

25. Clinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen 25 , Erlangen, Germany

26. Dept. of Pediatric Immunology and Pulmonology, Centre for Primary Immune Deficiency Ghent, Ghent University Hospital 26 , Ghent, Belgium

27. Dept. of Internal Medicine and Pediatrics, PID Research Laboratory, Ghent University 27 , Ghent, Belgium

28. Dept. of Immunology, University Hospital Marqués de Valdecilla, IDIVAL 28 , Santander, Spain

29. Dept. of Pediatric Oncohematology, Hospital Materno Infantil Torrecárdenas 29 , Almería, Spain

30. Division of Immunology and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; University of Zurich 30 , Zurich, Switzerland

31. Dept. of Pediatrics, CHU St Pierre, ULB/VUB 31 , Brussels, Belgium

32. Dept. of Internal Medicine, Unit of Infectious Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System 32 , Las Palmas de Gran Canaria, Spain

33. Dept. of Immunology, UGC Laboratories, University Hospital of Jaén 33 , Jaén, Spain

34. Pediatric Infectious Diseases Unit, Hospital Sant Joan de Déu 34 , Barcelona, Spain

35. CIBER of Epidemiology and Public Health, Madrid, Spain; Translational Research Network in Pediatric Infectious Diseases 35 , Madrid, Spain

36. Dept. of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, University of Barcelona 36 , Barcelona, Spain

37. Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe 37 , Curitiba, Brazil

38. Dept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria 38 , Las Palmas de Gran Canaria, Spain

39. Dept. of Respiratory Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System 39 , Las Palmas de Gran Canaria, Spain

40. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children 40 , Paris, France

41. University Paris Cité, Imagine Institute 41 , Paris, France

42. Pediatric Hematology and Immunology Unit, Department of Pediatrics, Necker Hospital for Sick Children, AP-HP 42 , Paris, France

43. Department of Pediatrics, Necker Hospital for Sick Children 43 , Paris, France

44. Howard Hughes Medical Institute 44 , New York, NY, USA

Abstract

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4–dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8–207.8, P < 0.001). The patients’ susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.

Funder

Instituto de Salud Carlos III

Spanish Ministry of Science and Innovation

Fundación Canaria Instituto de Investigación Sanitaria de Canarias

Grupo DISA

Fundación MAPFRE Guanarteme

Cabildo Insular de Tenerife

Convocatòria de Beques de Recerca IRSJD—Carmen de Torres 2022

CERCA Programme/Generalitat de Catalunya

Else Kröner-Fresenius-Stiftung

German Federal Ministry of Education and Research

National Institute of Allergy and Infectious Diseases