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1. Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

Author

Shen-Ying Zhang, Mélodie Aubart, Lazaro Lorenzo, Helen C. Su, Soraya Boucherit, Zhiyong Liu, Danyel Lee, Paul Bastard, Andrea Martín-Nalda, Jie Chen, Laurent Abel, Jeremy Manry, Pere Soler Palacín, Jean-Laurent Casanova, Jacques G. Rivière, Huie Jing, Mary Hasek, Flore Rozenberg, Roger Colobran, Wesley Tung, Université Paris Cité, Equipe HAL, APPEL À PROJETS GÉNÉRIQUE 2018 - Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est - - SEAe-HostFactors2018 - ANR-18-CE15-0020 - AAPG2018 - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Laboratory of Clinical Immunology and Microbiology [Bethesda, MA, USA] (LCIM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Vall d’Hebron Research Institute (VHIR), Vall d'Hebron University Hospital [Barcelona], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), and ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

Subjects
Male, Interferon-Induced Helicase, IFIH1, viruses, Immunology, chemical and pharmacologic phenomena, Interferon alpha-2, Biology, Virus Replication, medicine.disease_cause, Compound heterozygosity, Loss of Function Mutation, Immunity, Enterovirus Infections, medicine, Extracellular, Humans, Immunology and Allergy, Encephalitis, Viral, Cells, Cultured, Enterovirus, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Infant, MDA5, Interferon-beta, Fibroblasts, Virology, Toll-Like Receptor 3, Rhombencephalon, Poly I-C, Cell culture, Child, Preschool, TLR3, Female, Metabolism, Inborn Errors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Intracellular
Abstract

International audience; Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-β in the patients’ fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.

Published
2021
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2. TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

Author

Isabelle Meyts, Xin Mu, Emmanuelle Jouanguy, Daxing Gao, Aurélie Cobat, Lazaro Lorenzo, Mary Hasek, Damien Chaussabel, Luigi D. Notarangelo, Darragh Duffy, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Lorenz Studer, Gregory A. Smith, Sun Hur, Jie Chen, Peng Zhang, Michael J. Ciancanelli, Jessica L. McAlpine, Gabriele Ciceri, Shen-Ying Zhang, Oliver Harschnitz, Yuval Itan, Michael S. Diamond, Benedetta Bigio, Vincent Bondet, Esperanza Anguiano, Laurent Abel, Rockefeller University [New York], University of Science and Technology of China [Hefei] (USTC), Turnstone Biologics [New York], Memorial Sloane Kettering Cancer Center [New York], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Harvard Medical School [Boston] (HMS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Imperial College London, Baylor Institute for Immunology Research (BIIR), Benaroya Research Institute [Seattle] (BRI), Sidra Medicine [Doha, Qatar], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Feinberg School of Medicine, Northwestern University [Evanston], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute (HHMI), This work was funded in part by the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1TR001866), NIH (R01NS072381, R01AI088364, and R21AI151663), the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID), and grants ANR-14-CE14-0008-01 and ANR-18-CE15-0020-02, The Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. DG is supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and the National Natural Science Foundation of China (grant 31970855). IM is supported by KU Leuven C1 grant C16/18/007 and Fonds Wetenschappelijk Onderzoek Vlaanderen grant G0C8517N., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), Institut Pasteur [Paris] (IP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, viruses, NF-KAPPA-B, Herpesvirus 1, Human, Research & Experimental Medicine, RIG-I, Mice, 0302 clinical medicine, ADAPTER PROTEIN, Induced pluripotent stem cell, GENE-EXPRESSION, Cerebral Cortex, Mice, Knockout, Neurons, Innate immunity, Infectious disease, biology, virus diseases, VESICULAR STOMATITIS-VIRUS, General Medicine, 3. Good health, Cell biology, INTERFERON-ALPHA/BETA, Medicine, Research & Experimental, Vesicular stomatitis virus, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESSENGER-RNA, Life Sciences & Biomedicine, Research Article, HERPES-SIMPLEX ENCEPHALITIS, Immunology, chemical and pharmacologic phenomena, DOUBLE-STRANDED-RNA, Cell Line, 03 medical and health sciences, Immunity, Animals, Humans, Secretion, Messenger RNA, Science & Technology, Innate immune system, TOLL-LIKE RECEPTOR-3, Interferon-beta, Vesiculovirus, Fibroblasts, biology.organism_classification, Embryonic stem cell, Toll-Like Receptor 3, 030104 developmental biology, TLR3
Abstract

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:1 ispartof: location:United States status: published

Published
2021
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3. Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Author

Jeremy Manry, Eduardo J. Garcia Reino, Taushif Khan, Romain Lévy, Mary Hasek, Jérémie Rosain, Yoann Seeleuthner, Isabelle Meyts, Lazaro Lorenzo, Laurent Abel, Zhi Li, Omar AbuZaitun, Shai Shrot, Paul Bastard, Jean-Laurent Casanova, Bertrand Boisson, Emmanuelle Jouangy, Flore Rozenberg, Nicholas Hernandez, Raz Somech, Benedetta Bigio, Shen-Ying Zhang, Mélodie Aubart, Vivien Béziat, Nico Marr, Jie Chen, Rik Gijsbers, Peng Zhang, Jacinta Bustamante, Qian Zhang, Yoon-Seung Lee, Sandra Pellegrini, Aurélie Cobat, Soraya Boucherit, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Sidra Medicine [Doha, Qatar], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chaim Sheba Medical Center, Kfar Saba and Sackler School of Medicine, Service de neurochirurgie pédiatrique [CHU Necker], Faculté de Médecine et Médecine Dentaire [UCLouvain], Université Catholique de Louvain = Catholic University of Louvain (UCL), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hamad Bin Khalifa University (HBKU), Precision Immunology Institute [New-York] (PrIISM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program, grant UL1TR001866, NIH grants R01AI088364, R01NS072381 and R21AI151663, the National Vaccine Program Office of the US Department of Health and Human Services grant VSRNV000006, grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02), and CNSVIRGEN (ANR-19-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). JR was supported by the Inserm PhD program ('poste d’accueil Inserm'). JM was supported by ANR grants BURULIGEN (ANR-12-BSV3-0013-01) and MYCOPARADOX (ANR-16-CE12-0023)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), and ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019)

Subjects
Male, 0301 basic medicine, Untranslated region, Adolescent, [SDV]Life Sciences [q-bio], Immunology, Herpesvirus 1, Human, Receptor, Interferon alpha-beta, Biology, medicine.disease_cause, Rubella, 03 medical and health sciences, Exon, 0302 clinical medicine, Immunity, medicine, Humans, MESH: Receptor, Interferon alpha-beta, MESH: Interferons, Innate immunity, MESH: Adolescent, Infectious disease, MESH: Humans, MESH: Encephalitis, Herpes Simplex, MESH: Child, Preschool, General Medicine, medicine.disease, Virology, MESH: Male, MESH: Herpesvirus 1, Human, HEK293 Cells, 030104 developmental biology, Herpes simplex virus, Tyrosine kinase 2, Child, Preschool, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, Cytokines, Encephalitis, Herpes Simplex, Interferons, Viral disease, Encephalitis, Research Article, Genetic diseases
Abstract

International audience; Inborn errors of TLR3-dependent IFN-α/β– and IFN-λ–mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3′-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/β are essential for anti–HSV-1 immunity in the CNS

Published
2021
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4. Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis

Author

Zobaida Alsum, Soraya Boucherit, Lluis Quintana-Murci, Peng Zhang, Luigi D. Notarangelo, Joseph A. Church, Daxing Gao, Rabih Halwani, Lazaro Lorenzo, Thomas M. Carlile, Maria F. Rojas-Duran, Ahmed Aziz Bousfiha, Yuval Itan, Laurent Abel, Flore Rozenberg, Fabien G. Lafaille, Wendy V. Gilbert, Jean-Laurent Casanova, Vimel Rattina, Marc Tessier-Lavigne, Lorenz Studer, Trine H. Mogensen, Bastian Zimmer, Benoit Henry, Søren R. Paludan, Shen-Ying Zhang, Franck Rapaport, Gregory A. Smith, Saleh Al-Muhsen, Michael J. Ciancanelli, Gaspard Kerner, Jessica L. McAlpine, Kerry Dobbs, Madalina E. Carter-Timofte, Laura Marques, Oliver Harschnitz, Osefame Ewaleifoh, Mary Hasek, Dominik Paquet, Marc Tardieu, Naima Amenzoui, Yoon Seung Lee, Dylan Kwart, Rockefeller University [New York], Memorial Sloane Kettering Cancer Center [New York], Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Northwestern University Feinberg School of Medicine, Aarhus University Hospital, National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Sharjah, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., King Saud University [Riyadh] (KSU), Centro Hospitalar do Porto, University of Southern California (USC), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Stanford University, This work was funded in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Clinical and Translational Science Award program (grant nos. UL1TR000043 and UL1TR001866), NIH grants (nos. R01AI088364 to J.L.C. and S.Y.Z., R01NS072381 to J.-L.C. and S.-Y.Z. and R01GM101316 to W.G.), a grant from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (no. ANR-10-LABX-62-IBEID to L.A.) and the French National Research Agency (ANR) under the ‘Investments for the future’ program (no. ANR-10-IAHU-01 to L.A.), the ANR grant IEIHSEER (no. ANR-14-CE14-0008-01 to S.-Y.Z.), the Lundbeck Foundation (grant no. R268-2016-3927 to S.R.P.), the Rockefeller University, INSERM, Paris Descartes University and the St Giles Foundation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Hôpital Cochin [AP-HP], Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Southern California [Los Angeles, CA, USA], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Central Nervous System, Male, 0301 basic medicine, Intrinsic immunity, viruses, Central nervous system, Herpesvirus 1, Human, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Interferon, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, RNA, Small Nucleolar, Genetic Predisposition to Disease, Small nucleolar RNA, Neurons, Immunity, Infant, RNA, General Medicine, Middle Aged, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, 030220 oncology & carcinogenesis, Forebrain, Metagenome, Female, Encephalitis, Herpes Simplex, Small nuclear RNA, medicine.drug
Abstract

International audience; Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/β stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.

Published
2019
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5. Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection

Author

Anat Biran, Masad J. Damha, Michael J. Ciancanelli, Kerry Dobbs, Amos Etzioni, Osamu Ohara, Luísa Diogo, Mary Hasek, Stacy A. Hussong, Fabien G. Lafaille, Jean-Laurent Casanova, Yuval Itan, Lorenz Studer, Satoshi Okada, William G. Fairbrother, Lazaro Lorenzo, Veronica Galvan, Saleh Al-Muhsen, Gregory A. Smith, Rabih Halwani, Alexandra Dinis, Allison J Taggart, Aurélie Cobat, Nathaniel E. Clark, P. John Hart, Eduardo J. Garcia Reino, Brad R. Rosenberg, Luigi D. Notarangelo, Nicholas DeRosa, Adam Katolik, Emília Faria, Sonoko Sakata, Rie Fukuhara, Paula Garcia, Candice E. Van Skike, Maki Hyodo, Masao Kobayashi, Bastian Zimmer, Karen McCammon, Catherine A. Freije, Shen-Ying Zhang, Hanna Mandel, Jef D. Boeke, Miyuki Tsumura, Jingchuan Luo, Stephen P. Holloway, Elodie Pauwels, Laurent Abel, and Stefano Volpi

Subjects
0301 basic medicine, Male, Genetics and Molecular Biology (all), viruses, Mutant, viral encephalitis, Herpesvirus 1, Human, Biology, medicine.disease_cause, Virus Replication, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Virus, Article, brainstem, 03 medical and health sciences, Mice, Open Reading Frames, Immunity, medicine, Escherichia coli, DBR1, Animals, Humans, Amino Acid Sequence, Encephalitis, Viral, Allele, Alleles, RNA lariat debranching, Biochemistry, Genetics and Molecular Biology (all), RNA, Brain Diseases, Metabolic, Inborn, RNA Nucleotidyltransferases, Fibroblasts, Virology, Introns, Pedigree, Toll-Like Receptor 3, 030104 developmental biology, Herpes simplex virus, Mutation, Lariat debranching enzyme, Female, Mutant Proteins, Brainstem, Interferons, Brain Stem
Abstract

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients’ fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.

Published
2018

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