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研究揭示人SNORA31在神经元中的功能
作者:小柯机器人 发布时间:2019/12/6 11:37:51

美国洛克菲勒大学Shen-Ying Zhang、Jean-Laurent Casanova等人的研究显示,人SNORA31基因变异削弱了大脑皮层神经元对单纯疱疹病毒1(HSV-1)的固有免疫力,并为单纯疱疹病毒性脑炎发生提供了基础。相关论文2019年12月5日在线发表在《自然—医学》上。

研究人员对5名不相关前脑HSV-1脑炎(HSE)患者进行研究,每个患者的SNORA31基因是含有四个罕见变体之一的杂合子,编码H / ACA类的核仁小RNA,可能指导核小RNA和核糖体RNA中尿苷残基异构化为伪尿苷。研究结果显示,利用CRISPR / Cas9引入双或单等位基因SNORA31缺失可使人多能干细胞(hPSC)衍生的皮质神经元对HSV-1敏感。

因此,SNORA31突变患者的hPSC衍生皮质神经元对HSV-1敏感,就像那些来自TLR3或STAT1缺陷患者的一样。外源干扰素(IFN)-β使SNORA31-和TLR3-而不是STAT1突变的神经元对HSV-1具有抗性。最后,对SNORA31突变神经元的转录组分析显示,其对TLR3和IFN-α/β的刺激反应正常,但对HSV-1的反应异常。

人SNORA31通过独特的机制控制中枢神经系统神经元的固有免疫抵抗HSV-1。

据介绍,HSE通常是偶尔发生的。TLR3和DBR1介导的中枢神经系统细胞内源性免疫的先天性错误可分别导致前脑和脑干HSE。

附:英文原文

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

Author: 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, Kerry Dobbs, Bastian Zimmer, Daxing Gao, Maria F. Rojas-Duran, Dylan Kwart, Vimel Rattina, Michael J. Ciancanelli, Jessica L. McAlpine, Lazaro Lorenzo, Soraya Boucherit, Flore Rozenberg, Rabih Halwani, Benoit Henry, Naima Amenzoui, Zobaida Alsum, Laura Marques, Joseph A. Church, Saleh Al-Muhsen, Marc Tardieu, Ahmed Aziz Bousfiha, Sren R. Paludan, Trine Hyrup Mogensen, Lluis Quintana-Murci, Marc Tessier-Lavigne, Gregory A. Smith, Luigi D. Notarangelo, Lorenz Studer, Wendy Gilbert, Laurent Abel, Jean-Laurent Casanova, Shen-Ying Zhang

Issue&Volume: 2019-12-05

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.

DOI: 10.1038/s41591-019-0672-3

Source: https://www.nature.com/articles/s41591-019-0672-3

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex