Journal Article

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

Marques, Laura, Zhang, Peng, Boucherit, Soraya, Tessier-Lavigne, Marc, Ciancanelli, Michael J, Ahmed Aziz Bousfiha, Zimmer, Bastian, Mogensen, Trine Hyrup, Shen-Ying, Zhang, Kwart, Dylan, Rozenberg, Flore, Itan, Yuval, Notarangelo, Luigi D, Amenzoui, Naima, Jean-Laurent Casanova, Kerner, Gaspard, Lafaille, Fabien G, Harschnitz, Oliver, Ewaleifoh, Osefame, Halwani, Rabih, Hasek, Mary L, Paquet, Dominik, Tardieu, Marc, Paludan, Søren R, Rattina, Vimel, Yoon Seung Lee, Al-Muhsen, Saleh, Dobbs, Kerry, Studer, Lorenz, Carter-Timofte, Madalina E, Quintana-Murci, Lluis, Gao, Daxing, Church, Joseph A, Gilbert, Wendy, Rapaport, Franck, Smith, Gregory A, Carlile, Thomas M, Abel, Laurent, McAlpine, Jessica L, Alsum, Zobaida, Benoit, Henry, Rojas-Duran, Maria F, Lazaro, Lorenzo

2019

Overview

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: Nature Publishing Group
• Subject: Brain stem / Central nervous system / CRISPR / Encephalitis / Forebrain / Gene expression / Herpes simplex / Herpes viruses / Human behavior / Immunity / Interferon / Isomerization / Nervous system / Neurons / Nucleoli / Pluripotency / rRNA / snoRNA / snRNA / Stat1 protein / Stem cells / TLR3 protein / Toll-like receptors / Uridine / Viruses / α-Interferon