期刊
NATURE MEDICINE
卷 25, 期 12, 页码 1873-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0672-3
关键词
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资金
- National Center for Advancing Translational Sciences, National Institutes of Health (NIH) [UL1TR000043, UL1TR001866]
- NIH [R01AI088364, R01NS072381, R01GM101316]
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- French National Research Agency (ANR) [ANR-10-IAHU-01]
- ANR [ANR-14-CE14-0008-01]
- Lundbeck Foundation [R268-2016-3927]
- Rockefeller University
- INSERM
- Paris Descartes University
- St Giles Foundation
- New York Stem Cell Foundation
- Merck
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH
- Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0008] Funding Source: Agence Nationale de la Recherche (ANR)
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)-beta 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-alpha/beta 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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