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

Fabien Lafaille 1 Oliver Harschnitz 2 Yoon Seung Lee 1, 3, 4 Peng Zhang 1 Mary Hasek 1 Gaspard Kerner 3, 4 Yuval Itan Osefame Ewaleifoh 5 Franck Rapaport 2 Thomas Carlile Madalina Carter-Timofte 6 Dominik Paquet Kerry Dobbs 7 Bastian Zimmer Daxing Gao 1 Maria Rojas-Duran 8 Dylan Kwart 1 Vimel Rattina 4 Michael Ciancanelli 1 Jessica Mcalpine Lazaro Lorenzo 4 Soraya Boucherit 4 Flore Rozenberg 9 Rabih Halwani 10 Benoît Henry 11 Naima Amenzoui 12 Zobaida Alsum 13 Laura Marqués 14 Joseph Church 15 Saleh Al-Muhsen Marc Tardieu 16 Ahmed Aziz Bousfiha Søren Paludan 6 Trine Hyrup Mogensen 6 Lluis Quintana-Murci 17 Marc Tessier-Lavigne 18 Gregory Smith 5 Luigi Notarangelo 7 Lorenz Studer 2 Wendy Gilbert 8 Laurent Abel 1, 4 Jean-Laurent Casanova 3, 1 Shen-Ying Zhang 1, 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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Submitted on : Tuesday, April 21, 2020 - 5:19:39 PM
Last modification on : Thursday, October 20, 2022 - 3:10:07 PM

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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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