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

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

  • Nat Med. 2019 Dec;25(12):1873-1884. doi: 10.1038/s41591-019-0672-3.
Fabien G Lafaille 1,  Oliver Harschnitz 2 3,  Yoon Seung Lee 1 4 5,  Peng Zhang 1,  Mary L Hasek 1,  Gaspard Kerner 4 5,  Yuval Itan 1 6 7,  Osefame Ewaleifoh 8,  Franck Rapaport 1,  Thomas M Carlile 9,  Madalina E Carter-Timofte 10 11,  Dominik Paquet 12 13 14,  Kerry Dobbs 15,  Bastian Zimmer 2 3,  Daxing Gao 1,  Maria F Rojas-Duran 16,  Dylan Kwart 12,  Vimel Rattina 4 5,  Michael J Ciancanelli 1,  Jessica L McAlpine 2 3,  Lazaro Lorenzo 4 5,  Soraya Boucherit 4 5,  Flore Rozenberg 17,  Rabih Halwani 18,  Benoit Henry 19,  Naima Amenzoui 20,  Zobaida Alsum 21,  Laura Marques 22,  Joseph A Church 23,  Saleh Al-Muhsen 24,  Marc Tardieu 25,  Ahmed Aziz Bousfiha 20,  Søren R Paludan 11,  Trine Hyrup Mogensen 10 11 26,  Lluis Quintana-Murci 27,  Marc Tessier-Lavigne 9 28,  Gregory A Smith 8,  Luigi D Notarangelo 15,  Lorenz Studer 2 3,  Wendy Gilbert 16,  Laurent Abel 1 4 5,  Jean-Laurent Casanova 29 30 31 32 33,  Shen-Ying Zhang 34 35 36
Affiliations

Affiliations

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

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