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.
Original language | English (US) |
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Pages (from-to) | 1873-1884 |
Number of pages | 12 |
Journal | Nature Medicine |
Volume | 25 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2019 |
Funding
We warmly thank the patients and their families for participating in this study. We thank F. Sami Alkuraya from the Saudi Human Genome Project for providing us with the minor allele frequency of the reported variant. We thank J. Tchieu and G. Ciceri for providing advice concerning the protocol for iPSC differentiation into CNS neurons. We thank K. Bohannon from the Feinberg School of Medicine at Northwestern University for providing HSV-1 strain Patton encoding the mCherry-UL25 fusion. We thank members of both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions: T. Kochetkov for technical assistance; B. Bigio, V. Ratinna, Y. Seeleuthner, B. Boisson and A. Cobat for bioinformatic assistance; and D. Papandrea, C. Patissier and Y. Nemirovskaya for administrative assistance. This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Clinical and Translational Science Award program (grant nos. UL1TR000043 and UL1TR001866), NIH grants (nos. R01AI088364 to J.L.C. and S.Y.Z., R01NS072381 to J.-L.C. and S.-Y.Z. and R01GM101316 to W.G.); a grant from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (no. ANR-10-LABX-62-IBEID to L.A.) and the French National Research Agency (ANR) under the ‘Investments for the future’ program (no. ANR-10-IAHU-01 to L.A.), the ANR grant IEIHSEER (no. ANR-14-CE14-0008-01 to S.-Y.Z.), the Lundbeck Foundation (grant no. R268-2016-3927 to S.R.P.), the Rockefeller University, INSERM, Paris Descartes University and the St Giles Foundation. The New York Stem Cell Foundation supported F.G.L. and D.P. F.G.L. also was supported by a Merck Postdoctoral Fellowship at The Rockefeller University. Funding for this work was also provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology