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Lafaille, Fabien G.; Harschnitz, Oliver; Lee, Yoon Seung; Zhang, Peng; Hasek, Mary L.; Kerner, Gaspard; Itan, Yuval; Ewaleifoh, Osefame; Rapaport, Franck; Carlile, Thomas M.; Carter-Timofte, Madalina E.; Paquet, Dominik; Dobbs, Kerry; Zimmer, Bastian; Gao, Daxing; Rojas-Duran, Maria F.; Kwart, Dylan; Rattina, Vimel; Ciancanelli, Michael J.; McAlpine, Jessica L.; Lorenzo, Lazaro; Boucherit, Soraya; Rozenberg, Flore; Halwani, Rabih; Henry, Benoit; Amenzoui, Naima; Alsum, Zobaida; Marques, Laura; Church, Joseph A.; Al-Muhsen, Saleh; Tardieu, Marc; Bousfiha, Ahmed Aziz; Paludan, Soren R.; Mogensen, Trine Hyrup; Quintana-Murci, Lluis; Tessier-Lavigne, Marc; Smith, Gregory A.; Notarangelo, Luigi D.; Studer, Lorenz; Gilbert, Wendy; Abel, Laurent; Casanova, Jean-Laurent and Zhang, Shen-Ying (2019): Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. In: Nature Medicine, Vol. 25, No. 12

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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)-beta 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-alpha/beta 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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