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

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.,
  • Zhang S.

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.

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