Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis - Institut Pasteur Access content directly
Journal Articles Nature Medicine Year : 2019

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

Peng Zhang
Mary Hasek
Yuval Itan
  • Function : Author
Thomas Carlile
  • Function : Author
Dominik Paquet
  • Function : Author
Kerry Dobbs
Bastian Zimmer
  • Function : Author
Jessica Mcalpine
  • Function : Author
Flore Rozenberg
Rabih Halwani
  • Function : Author
  • PersonId : 938253
Benoît Henry
Saleh Al-Muhsen
  • Function : Author
  • PersonId : 938246
Ahmed Aziz Bousfiha
  • Function : Author
Trine Hyrup Mogensen

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.

Dates and versions

pasteur-02549798 , version 1 (21-04-2020)

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Fabien Lafaille, Oliver Harschnitz, Yoon Seung Lee, Peng Zhang, Mary Hasek, et al.. Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nature Medicine, 2019, 25 (12), pp.1873-1884. ⟨10.1038/s41591-019-0672-3⟩. ⟨pasteur-02549798⟩
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