Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis.
Lafaille FG, Harschnitz O, Lee YS, Zhang P, Hasek ML, Kerner G, Itan Y, Ewaleifoh O, Rapaport F, Carlile TM, Carter-Timofte ME, Paquet D, Dobbs K, Zimmer B, Gao D, Rojas-Duran MF, Kwart D, Rattina V, Ciancanelli MJ, McAlpine JL, Lorenzo L, Boucherit S, Rozenberg F, Halwani R, Henry B, Amenzoui N, Alsum Z, Marques L, Church JA, Al-Muhsen S, Tardieu M, Bousfiha AA, Paludan SR, Mogensen TH, Quintana-Murci L, Tessier-Lavigne M, Smith GA, Notarangelo LD, Studer L, Gilbert W, Abel L, Casanova JL, Zhang SY.
2019 Dec 6
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.