Yi-Hao Chan, Vanja Lundberg, Jérémie Le Pen, Jiayi Yuan, Danyel Lee, Francesca Pinci, Stefano Volpi, Koji Nakajima, Vincent Bondet, Sanna Åkesson, Noopur V Khobrekar, Aaron Bodansky, Likun Du, Tina Melander, Alice-Andrée Mariaggi, Yoann Seeleuthner, Tariq Shikh Saleh, Debanjana Chakravarty, Per Marits, Kerry Dobbs, Sofie Vonlanthen, Viktoria Hennings, Karolina Thörn, Darawan Rinchai, Lucy Bizien, Matthieu Chaldebas, Ali Sobh, Tayfun Özçelik, Sevgi Keles, Suzan A AlKhater, Carolina Prando, Isabelle Meyts, Michael R Wilson, Jérémie Rosain, Emmanuelle Jouanguy, Mélodie Aubart, Laurent Abel, Trine H Mogensen, Qiang Pan-Hammarström, Daxing Gao, Darragh Duffy, Aurélie Cobat, Stefan Berg, Luigi D Notarangelo, Oliver Harschnitz, Charles M Rice, Lorenz Studer, Jean-Laurent Casanova, Olov Ekwall, Shen-Ying Zhang
{"title":"SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.","authors":"Yi-Hao Chan, Vanja Lundberg, Jérémie Le Pen, Jiayi Yuan, Danyel Lee, Francesca Pinci, Stefano Volpi, Koji Nakajima, Vincent Bondet, Sanna Åkesson, Noopur V Khobrekar, Aaron Bodansky, Likun Du, Tina Melander, Alice-Andrée Mariaggi, Yoann Seeleuthner, Tariq Shikh Saleh, Debanjana Chakravarty, Per Marits, Kerry Dobbs, Sofie Vonlanthen, Viktoria Hennings, Karolina Thörn, Darawan Rinchai, Lucy Bizien, Matthieu Chaldebas, Ali Sobh, Tayfun Özçelik, Sevgi Keles, Suzan A AlKhater, Carolina Prando, Isabelle Meyts, Michael R Wilson, Jérémie Rosain, Emmanuelle Jouanguy, Mélodie Aubart, Laurent Abel, Trine H Mogensen, Qiang Pan-Hammarström, Daxing Gao, Darragh Duffy, Aurélie Cobat, Stefan Berg, Luigi D Notarangelo, Oliver Harschnitz, Charles M Rice, Lorenz Studer, Jean-Laurent Casanova, Olov Ekwall, Shen-Ying Zhang","doi":"10.1084/jem.20231725","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256911/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1084/jem.20231725","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/18 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
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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