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

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

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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.

Original languageEnglish
Pages (from-to)1873-1884
Number of pages12
JournalNature Medicine
Issue number12
StatePublished - 1 Dec 2019


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