ArticleThe Journal of experimental medicine2023
Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.
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Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 56 citations in OpenAlex.
- The emerging role of TLR7-mediated signaling in respiratory viral infections and autoimmune diseases.Cellular and molecular life sciences : CMLS · 2026Review
- Mechanisms and clinical research progress of IL-6-mediated crosstalk between the alveolar microenvironment and the immune system in patients with severe pneumonia undergoing mechanical ventilation.Frontiers in immunology · 2026Review
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- The seven enigmas of SARS-CoV-2: from the past to the future.Journal of human immunity · 2025Article
- Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections.Nature immunology · 2025Article
- The impact of genetic immune disorders on infections including COVID-19, inflammatory bowel disease and cancer.Nature immunology · 2025Review
- Pulmonary and Immune Dysfunction in Pediatric Long COVID: A Case Study Evaluating the Utility of ChatGPT-4 for Analyzing Scientific Articles.Journal of clinical medicine · 2025Review
- The monogenic landscape of human infectious diseases.The Journal of allergy and clinical immunology · 2025Review
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- Proteomic Analyses in COVID-19-Associated Secondary Hemophagocytic Lymphohistiocytosis.Critical care explorations · 2025Observational
- Human genetic and immunological determinants of SARS-CoV-2 infection and multisystem inflammatory syndrome in children.Clinical and experimental immunology · 2025Review
- Learning from inborn errors of immunity and secondary immune deficiencies about vaccine immunogenicity, efficacy, and safety.Clinical and experimental immunology · 2025Review
- Unraveled role of TLR7-mediated interferon signaling activation in COVID-19.Frontiers in cellular and infection microbiology · 2025Review
- Modulation of IRAK4 as a therapeutic strategy against monosodium urate- and xanthine-induced inflammation in macrophages and HepG2 cells.Frontiers in immunology · 2025Article
- Case Report: Novel variants in theFrontiers in immunology · 2025Article
- Three Unrelated Patients of Roma Ethnicity from a Single Center Carrying the Same Deletion inLife (Basel, Switzerland) · 2024Article
- The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond.Cellular & molecular immunology · 2024Review
- A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist.PLoS biology · 2024Article
- Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
57 authors at 20 institutions in 9 countries.
Ana García-GarcíaPediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona , Barcelona, Spain.ORCID 0000-0002-9900-9376
Rebeca Pérez de Diego *Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital , Madrid, Spain.ORCID 0000-0001-8426-8765
Carlos Flores *Genomics Division, Instituto Tecnológico y de Energías Renovables , Santa Cruz de Tenerife, Spain.ORCID 0000-0001-5352-069X
Darawan RinchaiSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0001-8851-7730
Jordi Solé-ViolánCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III , Madrid, Spain.ORCID 0000-0002-0483-4470
Àngela Deyà-MartínezPediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona , Barcelona, Spain.ORCID 0000-0002-8026-7674
Blanca García-SolisLaboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital , Madrid, Spain.ORCID 0000-0002-3718-2560
José M Lorenzo-SalazarGenomics Division, Instituto Tecnológico y de Energías Renovables , Santa Cruz de Tenerife, Spain.ORCID 0000-0002-5135-2861
Elisa Hernández-BritoDept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain.ORCID 0000-0002-8435-6885
Anna-Lisa LanzDept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München , Munich, Germany.ORCID 0000-0002-2933-1167
Leen MoensLaboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven , Leuven, Belgium.ORCID 0000-0002-5347-6526
Giorgia BucciolLaboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven , Leuven, Belgium.ORCID 0000-0001-5004-0738
Mohamed AlmuqamamDept. of Pediatrics, Drexel University College of Medicine, St Christopher's Hospital for Children , Philadelphia, PA, USA.ORCID 0000-0002-9011-0830
Joseph B DomachowskeDept. of Pediatrics, SUNY Upstate Medical University , Syracuse, NY, USA.ORCID 0000-0003-1510-1309
Elena ColinoUnidad de Enfermedades Infecciosas, Complejo Hospitalario Universitario Insular-Materno Infantil , Las Palmas de Gran Canaria, Spain.ORCID 0000-0002-9299-0800
Juan Luis Santos-PerezUnidad de Gestión Clínica de Pediatría y Cirugía Pediátrica, Hospital Virgen de las Nieves-IBS , Granada, Spain.ORCID 0000-0002-7654-961X
Francisco M MarcoDept. of Immunology, Alicante University General Hospital Doctor Balmis , Alicante, Spain.ORCID 0000-0001-5113-3637
Claudio PignataDept. of Translational Medical Sciences, Section of Pediatrics, Federico II University , Naples, Italy.ORCID 0000-0003-1568-9843
Aziz BousfihaDept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital , Casablanca, Morocco.ORCID 0000-0002-5011-9873
Stuart E TurveyDept. of Paediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0003-1599-1065
Stefanie BauerClinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen , Erlangen, Germany.ORCID 0000-0002-9155-9138
Filomeen HaerynckDept. of Pediatric Immunology and Pulmonology, Centre for Primary Immune Deficiency Ghent, Ghent University Hospital , Ghent, Belgium.ORCID 0000-0001-9161-7361
Javier Gonzalo Ocejo-VinyalsDept. of Immunology, University Hospital Marqués de Valdecilla, IDIVAL , Santander, Spain.ORCID 0000-0003-2245-4639
Francisco LendinezDept. of Pediatric Oncohematology, Hospital Materno Infantil Torrecárdenas , Almería, Spain.ORCID 0000-0002-1597-636X
Seraina PraderDivision of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; University of Zurich , Zurich, Switzerland.ORCID 0000-0002-2950-5411
Nora Naumann-BartschClinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen , Erlangen, Germany.ORCID 0000-0001-5606-9822
Jana Pachlopnik SchmidDivision of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; University of Zurich , Zurich, Switzerland.ORCID 0000-0002-6653-9047
Catherine M BiggsDept. of Paediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-4363-2660
Kyla HildebrandDept. of Paediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0003-3825-8202
Alexandra DreesmanDept. of Pediatrics, CHU St Pierre, ULB/VUB , Brussels, Belgium.ORCID 0000-0002-1885-7462
Miguel Ángel CárdenesDept. of Internal Medicine, Unit of Infectious Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain.ORCID 0000-0003-1633-6214
Fatima AilalDept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital , Casablanca, Morocco.ORCID 0000-0001-5824-3193
Ibtihal BenhsaienDept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital , Casablanca, Morocco.ORCID 0000-0001-5727-9629
Giuliana GiardinoDept. of Translational Medical Sciences, Section of Pediatrics, Federico II University , Naples, Italy.ORCID 0000-0002-0621-9527
Agueda Molina-FuentesDept. of Immunology, UGC Laboratories, University Hospital of Jaén , Jaén, Spain.ORCID 0000-0001-9686-6156
Claudia FortunyStudy Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona , Barcelona, Spain.ORCID 0000-0001-7182-5745
Swetha MadhavarapuDept. of Pediatrics, Drexel University College of Medicine, St Christopher's Hospital for Children , Philadelphia, PA, USA.ORCID 0000-0001-8121-4374
Daniel H ConwayDept. of Pediatrics, Drexel University College of Medicine, St Christopher's Hospital for Children , Philadelphia, PA, USA.ORCID 0000-0001-7930-4071
Carolina PrandoInstituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe , Curitiba, Brazil.ORCID 0000-0002-9570-9770
Laire SchidlowskiInstituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe , Curitiba, Brazil.ORCID 0000-0002-0452-0164
María Teresa Martínez de Saavedra ÁlvarezDept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain.ORCID 0000-0001-8579-226X
Rafael AlfaroDept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain.ORCID 0000-0002-8298-8918
Felipe Rodríguez de CastroDept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria , Las Palmas de Gran Canaria, Spain.ORCID 0000-0002-6812-2739
ESID Registry Working Party
COVID Human Genetic Effort
Isabelle MeytsLaboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven , Leuven, Belgium.ORCID 0000-0003-1214-0302
Fabian HauckDept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München , Munich, Germany.ORCID 0000-0001-9644-2003
Anne PuelSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0003-2603-0323
Paul BastardSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0002-5926-8437
Bertrand BoissonSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0001-5240-3555
Emmanuelle JouanguySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0002-7358-9157
Laurent AbelSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0001-7016-6493
Aurélie CobatLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France.ORCID 0000-0001-7209-6257
Qian Zhang *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0002-9040-3289
Jean-Laurent Casanova *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA.ORCID 0000-0002-7782-4169
Laia Alsina *Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona , Barcelona, Spain.ORCID 0000-0002-3559-0018
Carlos Rodríguez-Gallego *Dept. of Clinical Sciences, University Fernando Pessoa Canarias , Las Palmas de Gran Canaria, Spain.ORCID 0000-0002-4344-8644
Inserm · FRHospital Sant Joan de Déu Barcelona · ESHoward Hughes Medical Institute · USUniversidad de Las Palmas de Gran Canaria · ESUniversity of British Columbia · CAUniversity of Hassan II Casablanca · MAHospital La Paz Institute for Health Research · ESHospital Universitario de Gran Canaria Doctor Negrín · ESInstituto de Salud Carlos III · ESUniversitair Ziekenhuis Leuven · BEGhent University Hospital · BESt. Christopher's Hospital for Children · USFederico II University Hospital · ITHospital Universitario Virgen de las Nieves · ESUniversité Paris Cité · FRUniversity of Zurich · CHCentre Hospitalier Universitaire de Saint-Pierre · BEHospital General Universitario de Alicante Doctor Balmis · ESHospital Materno-Infantil · ESHospital Universitario Insular de Gran Canaria · ES
Funding
TRANSFORMING TRANSLATIONAL SCIENCE AND EDUCATION TO BENEFIT HUMAN HEALTHUL1RR024143 · NCRR · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY · 2006 to 2011
$49.1MDeveloping, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6MHost factors contributing to susceptibility to COVID-19 diseaseZIAAI001265 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI SU, HELEN CHUN-HUI · 2020 to 2025
$9.5MMonogenic basis of resistance to SARS-CoV2 and predisposition to severe COVID-19R01AI088364 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI Jean-Laurent Casanova, Shen-Ying Zhang · 2010 to 2026
$8.7MInborn errors of immunity in patients with life-threatening COVID-19R01AI163029 · NIAID · ROCKEFELLER UNIVERSITY · PI CASANOVA, JEAN-LAURENT, ZHANG, QIAN · 2021 to 2025
$3.7MCharacterization of host immune responses to SARS-CoV-2ZIAAI001270 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2020 to 2025
$1.2MHoward Hughes Medical InstituteMedical Research Council MR/S032304/1NCATS NIH HHS UL1 TR001866NCRR NIH HHS UL1 RR024143NIAID NIH HHS R01 AI088364NIAID NIH HHS R01 AI163029
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.
Indexed as
COVID-19Myeloid Differentiation Factor 88Adaptor Proteins, Signal TransducingChildHumansInterleukin-1 Receptor-Associated KinasesPrimary Immunodeficiency DiseasesSARS-CoV-2Toll-Like Receptor 7Adaptor Proteins, Signal TransducingInterleukin-1 Receptor-Associated KinasesIRAK4 protein, humanMYD88 protein, humanMyeloid Differentiation Factor 88Toll-Like Receptor 7
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