Wacher Christie, Müller Marcus, Hofer Markus J, Getts Daniel R, Zabaras Regina, Ousman Shalina S, Terenzi Fulvia, Sen Ganes C, King Nicholas J C, Campbell Iain L
School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW 2006, Australia.
J Virol. 2007 Jan;81(2):860-71. doi: 10.1128/JVI.01167-06. Epub 2006 Nov 1.
The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.
干扰素（IFN）刺激基因（ISG）ISG - 49、ISG - 54和ISG - 56对病毒感染高度敏感，然而这些基因在体内的调控和功能尚不清楚。我们研究了在小鼠感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）或西尼罗河病毒（WNV）期间，这些ISG在小鼠脑中的同时调控情况。在LCMV感染期间，ISG - 49和ISG - 56基因的表达显著增加，广泛且主要定位于常见以及不同的神经元群体。ISG - 54基因的表达也增加，但水平较低且分布更局限。尽管在感染LCMV的STAT1和STAT2基因敲除（KO）小鼠的脑中，ISG - 49、ISG - 54和ISG - 56基因的表达增加，但这种增加受到抑制、延迟，且局限于脉络丛、脑膜和内皮细胞。在野生型和STAT基因敲除小鼠的LCMV感染过程中，ISG - 56蛋白在脑中与相应的RNA转录本平行调控。在野生型小鼠感染WNV后，其脑中ISG - 49、ISG - 54和ISG - 56的RNA水平以及ISG - 56蛋白水平也出现了类似变化。因此，在LCMV和WNV感染期间，ISG - 49、ISG - 54和ISG - 56基因在脑中协同上调；对于LCMV而言，这种上调在完全程度上（神经元）或部分程度上（非神经元）依赖于IFN信号分子STAT1和STAT2。这些发现表明，ISG - 49、ISG - 54和ISG - 56基因在宿主对中枢神经系统中不同病毒的反应中起主导作用，尤其是在神经元中，这些基因可能具有非冗余功能。
