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

   


Authors: Lafaille, F. G.; Harschnitz, O.; Lee, Y. S.; Zhang, P.; Hasek, M. L.; Kerner, G.; Itan, Y.; Ewaleifoh, O.; Rapaport, F.; Carlile, T. M.; Carter-Timofte, M. E.; Paquet, D.; Dobbs, K.; Zimmer, B.; Gao, D.; Rojas-Duran, M. F.; Kwart, D.; Rattina, V.; Ciancanelli, M. J.; McAlpine, J. L.; Lorenzo, L.; Boucherit, S.; Rozenberg, F.; Halwani, R.; Henry, B.; Amenzoui, N.; Alsum, Z.; Marques, L.; Church, J. A.; Al-Muhsen, S.; Tardieu, M.; Bousfiha, A. A.; Paludan, S. R.; Mogensen, T. H.; Quintana-Murci, L.; Tessier-Lavigne, M.; Smith, G. A.; Notarangelo, L. D.; Studer, L.; Gilbert, W.; Abel, L.; Casanova, J. L.; Zhang, S. Y.
Article Title: Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis
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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: controlled study; human tissue; human cell; nonhuman; alpha interferon; gene; stat1 protein; genetic variation; heterozygote; cellular immunity; pluripotent stem cell; ribosome rna; forebrain; transcriptome; beta interferon; uridine; virus immunity; isomerization; brain nerve cell; small nuclear rna; pseudouridine; herpes simplex encephalitis; toll like receptor 3; human; priority journal; article; crispr-cas9 system; human alphaherpesvirus 1; snora31 gene
Journal Title: Nature Medicine
Volume: 25
Issue: 12
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2019-12-01
Start Page: 1873
End Page: 1884
Language: English
DOI: 10.1038/s41591-019-0672-3
PUBMED: 31806906
PROVIDER: scopus
PMCID: PMC7376819
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076130067&doi=10.1038%2fs41591-019-0672-3&partnerID=40&md5=ed95b6b280ba969a9a056e6e29f7ede7
Notes: Article -- Source: Scopus
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MSK Authors
  1. Lorenz Studer
    223 Studer
  2. Bastian Zimmer
    14 Zimmer
  3. Oliver Harschnitz
    11 Harschnitz
  4. Jessica L Mcalpine
    3 Mcalpine
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