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

HSV-1 encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system (CNS) 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 snoRNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in snRNA and rRNA. We show that CRISPR/Cas9-introduced biallelic and monoallelic SNORA31 deletions render human pluripotent stem cells (hPSCs)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSCs-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous IFN-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of the SNORA31-mutated neurons reveal normal responses to TLR3 and IFN-α/β stimulation, but abnormal responses to HSV-1. Human SNORA31 thus controls CNS neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.