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Nat Med. 2019 Dec;25(12):1873-1884. doi: 10.1038/s41591-019-0672-3. Epub 2019 Dec 5.

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
2
The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
3
Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
4
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Paris, France.
5
Paris Descartes University, Imagine Institute, Paris, France.
6
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
9
Biogen, Cambridge, MA, USA.
10
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
11
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
12
Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY, USA.
13
Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.
14
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
15
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
16
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
17
Virology Department, Paris Descartes University, Sorbonne Paris Cité University, Welfare Services Paris Hospital, Hospital Group Paris Center University, Paris, France.
18
Sharjah Institute for Medical Research (SIMR), Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
19
Department of Infectious Diseases, Pitié-Salpêtrière Hospital, Paris, France.
20
Clinical Immunology Unit, Children's Ibn Rushd Hospital and Clinical Immunology Laboratory, Inflammation and Allergy LICIA, Faculty of Medicine and Pharmacy, Hassan Ii University, Casablanca, Morocco.
21
Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
22
Pediatric Department, Infectious Diseases and Immunodeficiencies Unit, Porto Hospital Center, Porto, Portugal.
23
Department of Pediatrics, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
24
Prince Naif Center for Immunology Research, King Saud University, Riyadh, Saudi Arabia.
25
South Paris University Hospital, Paris Hospital Welfare Services, Department of Pediatric Neurology, Paris, France.
26
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
27
Unit of Human Evolutionary Genetics, CNRS UMR2000, Institut Pasteur, Paris, France.
28
Department of Biology, Stanford University, Stanford, CA, USA.
29
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. casanova@rockefeller.edu.
30
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Paris, France. casanova@rockefeller.edu.
31
Paris Descartes University, Imagine Institute, Paris, France. casanova@rockefeller.edu.
32
Pediatric Immuno-Hematology Unit, Necker Hospital for Sick Children, Paris, France. casanova@rockefeller.edu.
33
Howard Hughes Medical Institute, New York, NY, USA. casanova@rockefeller.edu.
34
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. shzh289@rockefeller.edu.
35
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Paris, France. shzh289@rockefeller.edu.
36
Paris Descartes University, Imagine Institute, Paris, France. shzh289@rockefeller.edu.

Abstract

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.

PMID:
31806906
DOI:
10.1038/s41591-019-0672-3

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