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

Nature Medicine, 2019-12, Vol.25 (12), p.1873-1884 [Peer Reviewed Journal]

COPYRIGHT 2019 Nature Publishing Group ;COPYRIGHT 2019 Nature Publishing Group ;Copyright Nature Publishing Group Dec 2019 ;Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 1078-8956 ;EISSN: 1546-170X ;EISSN: 1744-7933 ;DOI: 10.1038/s41591-019-0672-3 ;PMID: 31806906

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Title:
Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis
Author: Lafaille, Fabien G ; Harschnitz, Oliver ; Lee, Yoon Seung ; Zhang, Peng ; Hasek, Mary L ; Kerner, Gaspard ; Itan, Yuval ; Ewaleifoh, Osefame ; Rapaport, Franck ; Carlile, Thomas M ; Carter-Timofte, Madalina E ; Paquet, Dominik ; Dobbs, Kerry ; Zimmer, Bastian ; Gao, Daxing ; Rojas-Duran, Maria F ; Kwart, Dylan ; Rattina, Vimel ; Ciancanelli, Michael J ; McAlpine, Jessica L ; Lorenzo, Lazaro ; Boucherit, Soraya ; Rozenberg, Flore ; Halwani, Rabih ; Henry, Benoit ; Amenzoui, Naima ; Alsum, Zobaida ; Marques, Laura ; Church, Joseph A ; Al-Muhsen, Saleh ; Tardieu, Marc ; Bousfiha, Ahmed Aziz ; Paludan, Søren R ; Mogensen, Trine Hyrup ; Quintana-Murci, Lluis ; Tessier-Lavigne, Marc ; Smith, Gregory A ; Notarangelo, Luigi D ; Studer, Lorenz ; Gilbert, Wendy ; Abel, Laurent ; Casanova, Jean-Laurent ; Zhang, Shen-Ying
Subjects: Adult ; Brain stem ; Cellular immunity ; Central nervous system ; Central Nervous System - immunology ; Central Nervous System - virology ; Child, Preschool ; CRISPR ; Diagnosis ; Encephalitis ; Encephalitis, Herpes Simplex - genetics ; Encephalitis, Herpes Simplex - immunology ; Encephalitis, Herpes Simplex - pathology ; Encephalitis, Herpes Simplex - virology ; Female ; Forebrain ; Gene expression ; Genetic aspects ; Genetic Predisposition to Disease ; Genetic variation ; Genetics ; Health aspects ; Herpes simplex ; Herpes simplex encephalitis ; Herpes viruses ; Herpesvirus 1, Human - genetics ; Herpesvirus 1, Human - immunology ; Herpesvirus 1, Human - pathogenicity ; Human behavior ; Human genetics ; Human health and pathology ; Humans ; Immunity ; Immunity - genetics ; Infant ; Infectious diseases ; Interferon ; Isomerization ; Life Sciences ; Male ; Medical examination ; Metagenome - genetics ; Metagenome - immunology ; Middle Aged ; Nervous system ; Neurons ; Neurons - immunology ; Neurons - virology ; Nucleoli ; Pluripotency ; Prefrontal cortex ; RNA, Small Nucleolar - genetics ; RNA, Small Nucleolar - immunology ; rRNA ; snoRNA ; snRNA ; Stat1 protein ; Stem cells ; TLR3 protein ; Toll-like receptors ; Uridine ; Viruses ; α-Interferon
Is Part Of: Nature Medicine, 2019-12, Vol.25 (12), p.1873-1884
Description: 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.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1078-8956
EISSN: 1546-170X
EISSN: 1744-7933
DOI: 10.1038/s41591-019-0672-3
PMID: 31806906
Source: AUTh Library subscriptions: ProQuest Central
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Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis

COPYRIGHT 2019 Nature Publishing Group ;COPYRIGHT 2019 Nature Publishing Group ;Copyright Nature Publishing Group Dec 2019 ;Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 1078-8956 ;EISSN: 1546-170X ;EISSN: 1744-7933 ;DOI: 10.1038/s41591-019-0672-3 ;PMID: 31806906

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