Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses.
Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses.
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不同类型的神经元对西尼罗河病毒（WNV）感染的敏感性不同。Michael Diamond及其同事现在表明，小脑颗粒细胞神经元（GCN）比皮质神经元具有更高的I型干扰素诱导基因表达的基础水平，使GCN对各种正链RNA病毒（包括WNV）的感染更具抵抗力。本文的在线版本（doi：10.1038/nm.3108）包含补充材料，可供授权用户使用。虽然大脑神经元对微生物感染的易感性是临床结果的主要决定因素，但对控制这种易感性的分子因素知之甚少。在这里，我们表明，两种类型的神经元从不同的大脑区域表现出不同的perception几个正链RNA病毒的复制。小脑的颗粒细胞神经元和来自大脑皮层的皮层神经元具有独特的先天免疫程序，其赋予离体和体内对病毒感染的不同易感性。通过用在颗粒细胞神经元中表达更高的基因转导皮质神经元，我们确定了三个干扰素刺激的基因（ISG; Ifi 27，Irg 1和Rsad 2（也称为Viperin）），它们介导了对不同嗜神经病毒的抗病毒作用。此外，我们发现ISGs的表观遗传状态和microRNA（miRNA）介导的调节与颗粒细胞神经元中增强的抗病毒反应相关。因此，来自进化上不同的大脑区域的神经元具有独特的先天免疫特征，这可能有助于它们对感染的相对宽容。本文的在线版本（doi：10.1038/nm.3108）包含补充材料，可供授权用户使用。
Different types of neurons are differentially susceptible to West Nile virus (WNV) infection. Michael Diamond and colleagues now show that cerebellar granule cell neurons (GCN) have a higher basal level of expression of type I interferon–inducible genes than cortical neurons, making GCN more resistant to infection by a variety of positive-stranded RNA viruses, including WNV. The online version of this article (doi:10.1038/nm.3108) contains supplementary material, which is available to authorized users. Although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. Here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded RNA viruses. Granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptibility to viral infection ex vivo and in vivo. By transducing cortical neurons with genes that were expressed more highly in granule cell neurons, we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses. Moreover, we found that the epigenetic state and microRNA (miRNA)-mediated regulation of ISGs correlates with enhanced antiviral response in granule cell neurons. Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, which probably contribute to their relative permissiveness to infection. The online version of this article (doi:10.1038/nm.3108) contains supplementary material, which is available to authorized users.