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Human SNORA31 Variations Impair Cortical Neuron-Intrinsic Immunity to HSV-1 and Underlie Herpes Simplex Encephalitis

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, etc.

Nat Med. 2019 Dec;25(12):1873-1884.

PMID: 31806906

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248762	IFN-alpha 1 human			Price

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