ArticleThe Journal of experimental medicine2024
SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
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Article in The Journal of experimental medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed.
- Genetic mechanisms underlying host susceptibility to central nervous system viral infections.Current opinion in infectious diseases · 2026Review
- Toward a monogenic architecture of human infections: From 1996 to 2026.Journal of human immunity · 2026Review
- Defects in intron recycling suppress the antiviral response via a mechanism of intronic endogenous dsRNA.The Journal of experimental medicine · 2026Article
- Recurrent severe viral infection in a child with inherited complete TBK1 deficiency.Journal of human immunity · 2026Article
- Article
- Human inborn errors of type I interferon-independent intrinsic immunity in nonleukocytic cells.Current opinion in immunology · 2025Review
- The seven enigmas of SARS-CoV-2: from the past to the future.Journal of human immunity · 2025Article
- Pattern Recognition Receptors (PRRs) Expression and Activation in COVID-19 and Long COVID: From SARS-CoV-2 Escape Mechanisms to Emerging PRR-Targeted Immunotherapies.Microorganisms · 2025Review
- SARS-CoV-2 infection of substantia nigra pars compacta induces expression of miR-330-5p at 10 days post-infection.The Journal of general virology · 2025Article
- Human DBR1 deficiency impairs stress granule-dependent PKR antiviral immunity.The Journal of experimental medicine · 2025Article
- High mortality rates and long-term complications in children with infectious brainstem encephalitis: A study of sixteen cases.PloS one · 2025Article
- Review
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Authors and funding
51 authors.
Yi-Hao Chan *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0003-0329-238X
Vanja Lundberg *Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID 0009-0009-8012-230X
Jérémie Le Pen *Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.ORCID 0000-0001-7025-9526
Jiayi Yuan *The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research , New York, NY, USA.ORCID 0000-0001-8315-7609
Danyel Lee *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0003-3124-0245
Francesca Pinci *Human Technopole, Viale Rita Levi-Montalcini , Milan, Italy.ORCID 0000-0002-5013-9663
Stefano Volpi *Rheumatology and Autoinflammatory Diseases, IRCCS Giannina Gaslini Institute, Genoa, Italy.ORCID 0000-0002-7129-868X
Koji NakajimaSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0002-3548-5330
Vincent BondetTranslational Immunology Unit, Institut Pasteur, Paris City University , Paris, France.ORCID 0000-0002-6534-0984
Sanna ÅkessonDepartment of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID 0009-0009-1333-7220
Noopur V KhobrekarThe Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research , New York, NY, USA.ORCID 0000-0002-5772-7265
Aaron BodanskyDepartment of Pediatrics, Division of Critical Care, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0001-8943-8233
Likun DuDepartment of Medical Biochemistry and Biophysics, Division of Immunology, Karolinska Institutet, Stockholm, Sweden.ORCID 0000-0002-8448-2187
Tina MelanderDepartment of Pediatrics, Härnösand Hospital, Region Västernorrland, Sundsvall, Sweden.ORCID 0009-0009-8246-213X
Alice-Andrée MariaggiLaboratory of Virology, Assistance Publique-Hôpitaux de Paris (AP-HP), Cochin Hospital , Paris, France.ORCID 0000-0002-1677-2967
Yoann SeeleuthnerLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.ORCID 0009-0000-2670-6026
Tariq Shikh SalehDepartment of Pediatric Dentistry, Sundsvall, Region Västernorrland, Sundsvall, Sweden.ORCID 0009-0006-7859-0436
Debanjana ChakravartyWeill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA.ORCID 0000-0002-4607-9143
Per MaritsDepartment of Medicine, Huddinge, Hematology Unit, Therapeutic Immunology and Transfusion, Karolinska University Hospital, Stockholm, Sweden.ORCID 0000-0003-2439-5687
Kerry DobbsDivision of Intramural Research, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-3432-3137
Sofie VonlanthenDepartment of Medicine, Huddinge, Hematology Unit, Therapeutic Immunology and Transfusion, Karolinska University Hospital, Stockholm, Sweden.ORCID 0000-0002-6215-7631
Viktoria HenningsDepartment of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID 0000-0002-7789-8299
Karolina ThörnDepartment of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID 0009-0000-1185-283X
Darawan RinchaiSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0001-8851-7730
Lucy BizienLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.ORCID 0000-0001-9163-9122
Matthieu ChaldebasSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0002-4920-3947
Ali SobhDepartment of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt.ORCID 0000-0001-7047-076X
Tayfun ÖzçelikDepartment of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.ORCID 0000-0001-5937-1082
Sevgi KelesNecmettin Erbakan University , Konya, Turkey.ORCID 0000-0001-7344-8947
Suzan A AlKhaterCollege of Medicine, Imam Abdulrahman Bin Faisal University , Dammam, Saudi Arabia.ORCID 0000-0001-7315-6581
Carolina PrandoFaculty of Pequeno Príncipe, Pesquisa Pelé Pequeno Príncipe Institute , Curitiba, Brazil.ORCID 0000-0002-9570-9770
Isabelle MeytsDepartment of Pediatrics, University Hospitals Leuven, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.ORCID 0000-0003-1214-0302
COVID Human Genetic Effort
Michael R WilsonWeill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA.ORCID 0000-0002-8705-5084
Jérémie RosainSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0002-2822-161X
Emmanuelle JouanguySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0002-7358-9157
Mélodie AubartLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.ORCID 0000-0002-4383-7930
Laurent AbelSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0001-7016-6493
Trine H MogensenDepartment of Biomedicine, Aarhus University, Aarhus, Denmark.ORCID 0000-0002-1853-9704
Qiang Pan-HammarströmDepartment of Medical Biochemistry and Biophysics, Division of Immunology, Karolinska Institutet, Stockholm, Sweden.ORCID 0000-0003-1990-8804
Daxing GaoDivision of Life Science and Medicine, Department of General Surgery, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
Darragh DuffyTranslational Immunology Unit, Institut Pasteur, Paris City University , Paris, France.ORCID 0000-0002-8875-2308
Aurélie CobatLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.ORCID 0000-0001-7209-6257
Stefan BergDepartment of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID 0000-0001-9601-6573
Luigi D NotarangeloDivision of Intramural Research, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-8335-0262
Oliver Harschnitz *Human Technopole, Viale Rita Levi-Montalcini , Milan, Italy.ORCID 0000-0001-6496-881X
Charles M Rice *Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.ORCID 0000-0003-3087-8079
Lorenz Studer *The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research , New York, NY, USA.ORCID 0000-0003-0741-7987
Jean-Laurent Casanova *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0002-7782-4169
Olov Ekwall *Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID 0000-0002-4506-9955
Shen-Ying Zhang *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.ORCID 0000-0002-9449-3672
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MDeveloping, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6MUnderstanding B cell memory in response to diverse virus infectionsU19AI111825 · NIAID · ROCKEFELLER UNIVERSITY · PI BOURNAZOS, STYLIANOS · 2014 to 2023
$26.0MYale Center for Mendelian GenomicsUM1HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2016 to 2020
$14.8MStudy of the Cellular Basis of Herpes Simplex Encephalitis with hPSC-Derived CNS and PNS CellsR01NS072381 · NINDS · UT SOUTHWESTERN MEDICAL CENTER · PI Jean-Laurent Casanova, Shen-Ying Zhang · 2010 to 2026
$10.2MMonogenic 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
$8.7MType I interferon-stimulated genes and the antiviral immune responseR01AI091707 · NIAID · ROCKEFELLER UNIVERSITY · PI RICE, CHARLES M · 2011 to 2020
$5.5MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MInborn errors of immunity in patients with life-threatening COVID-19R01AI163029 · NIAID · ROCKEFELLER UNIVERSITY · PI CASANOVA, JEAN-LAURENT, ZHANG, QIAN · 2021 to 2025
$3.7MTracking SARS-CoV-2 one molecule at a time: Spatiotemporal investigation of coronavirus replication dynamics and host response in single cells in vitro and in vivoR01AI161444 · NIAID · ROCKEFELLER UNIVERSITY · PI Charles M Rice · 2022 to 2026
$3.1MHumoral Immune Mechanisms of Acute and Chronic Neurologic Sequelae of COVID-19R01NS125693 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PLEASURE, SAMUEL JEREMY, WILSON, MICHAEL R · 2022 to 2025
$2.3MCharacterization of host immune responses to SARS-CoV-2ZIAAI001270 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2020 to 2025
$1.2MA*STARBattersea & Bowery Advisory GroupBawd FoundationEuropean Molecular Biology Organization ALTF 380-2018European Society for ImmunodeficienciesEuropean Union's Horizon 2020 research and innovation program 824110Fisher Center for Alzheimer's Research FoundationFondation du SouffleFonds Wetenschappelijk Onderzoek G0B5120NFrench Foundation for Medical Research EQU201903007798French Ministry of Higher Education, Research, and Innovation MESRI-COVID-19French National Research Agency ANR-10-IAHU-01Genome Sequencing Program Coordinating CenterGeorge Mason UniversityG. Harold and Leila Y. Mathers Charitable FoundationGrandir - Fonds de solidarité pour l'enfanceHORIZON-HLTH-2021-DISEASE-04 101057100Howard Hughes Medical InstituteInstitut National de la Santé et de la Recherche MédicaleJeffrey Modell FoundationJPB FoundationKU Leuven C16/18/007Meyer FoundationNational Institute of Allergy and Infectious DiseasesNCATS NIH HHS UL1 TR001866NCI NIH HHS P30 CA008748NHGRI NIH HHS U24 HG008956NHGRI NIH HHS UM1 HG006504NHGRI NIH HHS UM1HG006504NIAID NIH HHS R01 AI088364NIAID NIH HHS R01 AI091707NIAID NIH HHS R01 AI161444NIAID NIH HHS R01 AI163029NIAID NIH HHS R21 AI160576NIAID NIH HHS U19 AI111825NIH HHS R01AI088364NIH HHS S10 OD018521NINDS NIH HHS R01 NS072381NINDS NIH HHS R01 NS125693Paris Cité UniversityRockefeller UniversitySCOR Corporate Foundation for ScienceSquare FoundationSt. Giles FoundationSwedish Government ALFGBG-965795Swedish Research Council 2018-02752Yale University S10OD018521
Abstract
Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
Indexed as
Brain StemCOVID-19NeuronsSARS-CoV-2AdolescentEncephalitis, ViralFibroblastsHumansMaleRhombencephalon
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