Age-dependent resistance to lethal alphavirus encephalitis in mice:: Analysis of gene expression in the central nervous system and identification of a novel interferon-inducible protective gene, mouse ISG12
Age-dependent resistance to lethal alphavirus encephalitis in mice:: Analysis of gene expression in the central nervous system and identification of a novel interferon-inducible protective gene, mouse ISG12
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DOI：
10.1128/jvi.76.22.11688-11703.2002
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发表时间：
2002-11-01
影响因子：
5.4
通讯作者：
Levine, B
中科院分区：
文献类型：
--
作者：
Labrada, L;Liang, XH;Levine, B
几种不同的哺乳动物嗜神经病毒会产生一种年龄相关性脑炎，其特征是年轻宿主的疾病更严重。为了阐明对致死性病毒性脑炎的年龄依赖性抵抗的潜在因素，我们比较了模拟感染或脑内感染的新生小鼠和断奶小鼠的中枢神经系统(CNS)基因表达。在1日龄小鼠，感染dsTE12Q可导致迅速致死的疾病，与高CNS病毒滴度和广泛的CNS细胞凋亡有关；而在4周龄小鼠，dsTE12Q感染导致无症状感染，CNS病毒滴度较低，未检测到CNS细胞凋亡。基因芯片对模拟感染的新生儿和断奶小鼠大脑的表达比较发现，许多基因的mRNA表达在发育过程中受到调控，其中包括一些凋亡调控基因，如促凋亡分子caspase-3和TRAF4，它们在发育过程中下调，以及神经保护性趋化因子Fractalkine，它们在出生后发育过程中上调。在神经毒力增强和病毒复制增加的同时，辛德比斯病毒感染1日龄小鼠比感染4周龄小鼠导致更多表达改变的宿主炎症基因和更大程度的宿主炎症基因表达水平的变化。只有一种炎症反应基因，一种类似于人ISG12的表达序列标签，在感染4周的小鼠脑中增加的幅度比感染I天的小鼠脑中增加的幅度更大。此外，我们发现加强神经元ISG12的表达导致Sindbis病毒诱导的新生小鼠死亡的显著延迟。总而言之，我们的数据确定了在中枢神经系统中受发育调控的基因，以及在不同年龄的小鼠大脑中对辛德比斯病毒感染做出反应的差异调控基因。
Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In I-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in I-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected I-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.