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SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
Chan, Yi-Hao; Lundberg, Vanja; Le Pen, Jérémie; Yuan, Jiayi; Lee, Danyel; Pinci, Francesca; Volpi, Stefano; Nakajima, Koji; Bondet, Vincent; Åkesson, Sanna; Khobrekar, Noopur V; Bodansky, Aaron; Du, Likun; Melander, Tina; Mariaggi, Alice-Andrée; Seeleuthner, Yoann; Saleh, Tariq Shikh; Chakravarty, Debanjana; Marits, Per; Dobbs, Kerry; Vonlanthen, Sofie; Hennings, Viktoria; Thörn, Karolina; Rinchai, Darawan; Bizien, Lucy; Chaldebas, Matthieu; Sobh, Ali; Özçelik, Tayfun; Keles, Sevgi; AlKhater, Suzan A; Prando, Carolina; Meyts, Isabelle; Wilson, Michael R; Rosain, Jérémie; Jouanguy, Emmanuelle; Aubart, Mélodie; Abel, Laurent; Mogensen, Trine H; Pan-Hammarström, Qiang; Gao, Daxing; Duffy, Darragh; Cobat, Aurélie; Berg, Stefan; Notarangelo, Luigi D; Harschnitz, Oliver; Rice, Charles M; Studer, Lorenz; Casanova, Jean-Laurent; Ekwall, Olov; Zhang, Shen-Ying.
Affiliation
  • Chan YH; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.
  • Lundberg V; Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Le Pen J; Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Yuan J; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • Lee D; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research , New York, NY, USA.
  • Pinci F; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.
  • Volpi S; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
  • Nakajima K; Paris City University, Imagine Institute , Paris, France.
  • Bondet V; Human Technopole, Viale Rita Levi-Montalcini , Milan, Italy.
  • Åkesson S; Rheumatology and Autoinflammatory Diseases, IRCCS Giannina Gaslini Institute, Genoa, Italy.
  • Khobrekar NV; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
  • Bodansky A; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.
  • Du L; Translational Immunology Unit, Institut Pasteur, Paris City University , Paris, France.
  • Melander T; Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Mariaggi AA; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research , New York, NY, USA.
  • Seeleuthner Y; Department of Pediatrics, Division of Critical Care, University of California San Francisco, San Francisco, CA, USA.
  • Saleh TS; Department of Medical Biochemistry and Biophysics, Division of Immunology, Karolinska Institutet, Stockholm, Sweden.
  • Chakravarty D; Department of Pediatrics, Härnösand Hospital, Region Västernorrland, Sundsvall, Sweden.
  • Marits P; Laboratory of Virology, Assistance Publique-Hôpitaux de Paris (AP-HP), Cochin Hospital , Paris, France.
  • Dobbs K; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
  • Vonlanthen S; Paris City University, Imagine Institute , Paris, France.
  • Hennings V; Department of Pediatric Dentistry, Sundsvall, Region Västernorrland, Sundsvall, Sweden.
  • Thörn K; Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA.
  • Rinchai D; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
  • Bizien L; Department of Medicine, Huddinge, Hematology Unit, Therapeutic Immunology and Transfusion, Karolinska University Hospital, Stockholm, Sweden.
  • Chaldebas M; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
  • Sobh A; Division of Intramural Research, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Özçelik T; Department of Medicine, Huddinge, Hematology Unit, Therapeutic Immunology and Transfusion, Karolinska University Hospital, Stockholm, Sweden.
  • Keles S; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
  • AlKhater SA; Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Prando C; Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Meyts I; Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Wilson MR; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
  • Rosain J; Paris City University, Imagine Institute , Paris, France.
  • Jouanguy E; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.
  • Aubart M; Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
  • Abel L; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
  • Mogensen TH; Necmettin Erbakan University , Konya, Turkey.
  • Pan-Hammarström Q; College of Medicine, Imam Abdulrahman Bin Faisal University , Dammam, Saudi Arabia.
  • Gao D; Department of Pediatrics, King Fahad University Hospital, Al-Khobar, Saudi Arabia.
  • Duffy D; Faculty of Pequeno Príncipe, Pesquisa Pelé Pequeno Príncipe Institute , Curitiba, Brazil.
  • Cobat A; Department of Pediatrics, University Hospitals Leuven, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
  • Notarangelo LD; Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA.
  • Harschnitz O; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
  • Rice CM; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.
  • Studer L; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
  • Casanova JL; Paris City University, Imagine Institute , Paris, France.
  • Ekwall O; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY, USA.
  • Zhang SY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
J Exp Med ; 221(9)2024 09 02.
Article in En | MEDLINE | ID: mdl-39023559
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Stem / SARS-CoV-2 / COVID-19 / Neurons Limits: Adolescent / Humans / Male Language: En Journal: J Exp Med Year: 2024 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Stem / SARS-CoV-2 / COVID-19 / Neurons Limits: Adolescent / Humans / Male Language: En Journal: J Exp Med Year: 2024 Document type: Article Affiliation country: United States