Type I interferon protects neurons from prions in in vivo models
Type I interferon protects neurons from prions in in vivo models
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DOI：
10.1093/brain/awz016
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发表时间：
2019-04-01
期刊：
影响因子：
14.5
通讯作者：
Nishida，Noriyuki
中科院分区：
文献类型：
--
作者：
Ishibashi，Daisuke;Homma，Takujiro;Nishida，Noriyuki
由正常的Prion蛋白结构转换产生的含有异常Prion蛋白的传染性Prion是人类包括CreutzFeldt-Jakob病在内的传染性海绵状脑病的原因。Prion是一种不具有基因组的感染性病原体，致病蛋白被认为不会引起任何免疫反应。尽管我们先前报道了干扰素调节因子3(IRF3)可能参与了普恩病毒疾病的发病机制，暗示了IRF3信号介导的宿主先天免疫反应的保护作用，但这一点仍有待澄清。在这里，我们研究了I型干扰素与IRF3激活和普恩病毒感染的相互作用，发现感染普恩病毒会抑制内源性干扰素的表达。相反，在AneX活体模型中使用重组干扰素治疗能够抑制Pron感染。此外，缺乏I型干扰素受体(干扰素α/β受体1亚单位)的细胞和小鼠对22L-Prion感染表现出更高的敏感性。此外，在vivoandex vivoprion感染模型中，选择性I型干扰素受体激动剂RO8191治疗可抑制Pron入侵，延长感染小鼠的生存时间。综上所述，这些数据表明，干扰素信号干扰了Pron的传播，一些干扰素刺激的基因可能在大脑中发挥保护作用。这些发现可能有助于制定与致命疾病作斗争的新战略。
Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in anex vivomodel was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, inin vivoandex vivoprion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases.