Université Catholique de Louvain, de Duve Institute, Brussels, Belgium.
J Virol. 2014 Apr;88(7):3874-84. doi: 10.1128/JVI.03018-13. Epub 2014 Jan 22.
We examined the antiviral response promoted by type I interferons (IFN) in primary mouse neurons. IFN treatment of neuron cultures strongly upregulated the transcription of IFN-stimulated genes but conferred a surprisingly low resistance to infection by neurotropic viruses such as Theiler's murine encephalomyelitis virus (TMEV) or vesicular stomatitis virus (VSV). Response of primary mouse neurons to IFN treatment was heterogeneous, as many neurons failed to express the typical IFN response marker Mx1 after IFN treatment. This heterogeneous response of primary neurons correlated with a low level of basal expression of IFN-stimulated genes, such as Stat1, that are involved in signal transduction of the IFN response. In addition, transcriptomic analysis identified 15 IFN-responsive genes whose expression was low in IFN-treated primary neurons compared to that of primary fibroblasts derived from the same mice (Dhx58, Gvin1, Sp100, Ifi203 isoforms 1 and 2, Irgm2, Lgals3bp, Ifi205, Apol9b, Ifi204, Ifi202b, Tor3a, Slfn2, Ifi35, Lgals9). Among these genes, the gene coding for apolipoprotein L9b (Apol9b) displayed antiviral activity against Theiler's virus when overexpressed in L929 cells or in primary neurons. Accordingly, knocking down Apol9b expression in L929 cells increased viral replication. Therefore, we identified a new antiviral protein induced by interferon, ApoL9b, whose lack of expression in primary neurons likely contributes to the high sensitivity of these cells to viral infection.
The type I interferon (IFN) response is an innate immune defense mechanism that is critical to contain viral infection in the host until an adaptive immune response can be mounted. Neurons are a paradigm for postmitotic, highly differentiated cells. Our data show that primary mouse neurons that are exposed to type I interferon remain surprisingly susceptible to viral infection. On one hand, the low level of basal expression of some factors in neurons might prevent a rapid response of these cells. On the other hand, some genes that are typically activated by type I interferon in other cell types are expressed at much lower levels in neurons. Among these genes is the gene encoding apolipoprotein L9, a protein that proved to have antiviral activity against the neurotropic Theiler's murine encephalomyelitis virus. Our data suggest important functional differences in the IFN response mounted by specific cell populations.
我们研究了 I 型干扰素（IFN）在原代小鼠神经元中促进的抗病毒反应。IFN 处理神经元培养物强烈地上调了 IFN 刺激基因的转录，但令人惊讶的是，对神经嗜性病毒（如 Theiler 的鼠脑脊髓炎病毒[TMEV]或水疱性口炎病毒[VSV]）的感染并没有提供很高的抗性。原代小鼠神经元对 IFN 处理的反应是异质的，因为许多神经元在 IFN 处理后未能表达典型的 IFN 反应标志物 Mx1。这种原代神经元的异质反应与 IFN 反应信号转导所涉及的 IFN 刺激基因（如 Stat1）的基础表达水平较低相关。此外，转录组分析确定了 15 个 IFN 反应基因，其在 IFN 处理的原代神经元中的表达水平低于从同一小鼠衍生的原代成纤维细胞（Dhx58、Gvin1、Sp100、Ifi203 异构体 1 和 2、Irgm2、Lgals3bp、Ifi205、Apol9b、Ifi204、Ifi202b、Tor3a、Slfn2、Ifi35、Lgals9）。在这些基因中，编码载脂蛋白 L9b（Apol9b）的基因在 L929 细胞或原代神经元中过表达时显示出针对 Theiler 病毒的抗病毒活性。相应地，在 L929 细胞中敲低 Apol9b 表达会增加病毒复制。因此，我们鉴定了一种由干扰素诱导的新的抗病毒蛋白，ApoL9b，其在原代神经元中的表达缺失可能导致这些细胞对病毒感染高度敏感。
I 型干扰素（IFN）反应是一种先天免疫防御机制，对于宿主控制病毒感染至关重要，直到能够产生适应性免疫反应。神经元是有丝分裂后、高度分化的细胞的典范。我们的数据表明，暴露于 I 型干扰素的原代小鼠神经元仍然容易受到病毒感染。一方面，神经元中某些因子的基础表达水平较低可能会阻止这些细胞的快速反应。另一方面，在其他细胞类型中通常由 I 型干扰素激活的一些基因在神经元中的表达水平要低得多。这些基因包括编码载脂蛋白 L9 的基因，该蛋白被证明对神经嗜性 Theiler 的鼠脑脊髓炎病毒具有抗病毒活性。我们的数据表明，特定细胞群体中 IFN 反应的功能存在重要差异。
