The role of myelin in Theiler's virus persistence in the central nervous system.
The role of myelin in Theiler's virus persistence in the central nervous system.
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DOI：
10.1371/journal.ppat.0030023
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发表时间：
2007-02
期刊：
影响因子：
6.7
通讯作者：
Brahic M
中科院分区：
文献类型：
--
作者：
Roussarie JP;Ruffié C;Brahic M
泰勒病毒是一种小核糖核酸病毒，在小鼠的中枢神经系统中终生存在，并引起脱髓鞘疾病，这是多发性硬化症的模型。该病毒首先感染神经元，但持续存在于白质胶质细胞中，主要是少突胶质细胞和巨噬细胞。病毒从神经元运输到神经胶质细胞的机制，以及少突胶质细胞和巨噬细胞在持久性中各自的作用尚不清楚。我们利用之前的发现，即颤抖小鼠（一种髓磷脂碱性蛋白基因（Mbp）缺失的突变体）对持续性感染具有抵抗力，来检查髓磷脂在持续性感染中的作用。使用免疫嵌合体，我们证明耐药性不是由免疫反应或炎症细胞有效招募到中枢神经系统介导的。通过体内和体外实验，我们表明该突变不会损害神经元、少突胶质细胞和巨噬细胞对病毒的许可性。我们证明，在野生型小鼠持续感染期间，病毒抗原存在于髓磷脂的细胞质通道中。使用视神经作为模型，我们表明病毒从视网膜神经节细胞的轴突运输到髓磷脂的细胞质通道，并且这种运输受到颤抖突变的损害。这些结果揭示了泰勒病毒的未曾怀疑的轴突到髓磷脂的运输以及髓磷脂/少突胶质细胞持续感染所发挥的重要作用。泰勒病毒持续存在于小鼠的中枢神经系统中，并引起一种类似于多发性硬化症（人类常见的脱髓鞘疾病）的慢性疾病。该病毒会感染神经元一到两周，但随后它会持续存在于白质、少突胶质细胞和巨噬细胞中。少突胶质细胞是中枢神经系统的髓鞘形成细胞。引人注目的是，在具有髓磷脂遗传缺陷的小鼠中，病毒可以正常感染神经元，但无法持续存在。了解这种突变小鼠缺乏持久性的原因应该可以查明导致持久性的复杂过程中的一个重要步骤。在本文中，我们表明对持续感染的抵抗力不是由免疫系统介导的，也不是由于少突胶质细胞或巨噬细胞中病毒复制效率低下所致。相反，我们表明病毒通过轴突运输进入髓磷脂，并且这种运输被髓磷脂突变中断。泰勒病毒这种未曾预料到的轴突到髓鞘的运输对于病毒的持续存在是必要的。我们的研究结果证明，在其他神经系统持续感染（包括人类）中寻找类似的现象是有必要的。
Theiler's virus, a picornavirus, persists for life in the central nervous system of mouse and causes a demyelinating disease that is a model for multiple sclerosis. The virus infects neurons first but persists in white matter glial cells, mainly oligodendrocytes and macrophages. The mechanism, by which the virus traffics from neurons to glial cells, and the respective roles of oligodendrocytes and macrophages in persistence are poorly understood. We took advantage of our previous finding that the shiverer mouse, a mutant with a deletion in the myelin basic protein gene (Mbp), is resistant to persistent infection to examine the role of myelin in persistence. Using immune chimeras, we show that resistance is not mediated by immune responses or by an efficient recruitment of inflammatory cells into the central nervous system. With both in vivo and in vitro experiments, we show that the mutation does not impair the permissiveness of neurons, oligodendrocytes, and macrophages to the virus. We demonstrate that viral antigens are present in cytoplasmic channels of myelin during persistent infection of wild-type mice. Using the optic nerve as a model, we show that the virus traffics from the axons of retinal ganglion cells to the cytoplasmic channels of myelin, and that this traffic is impaired by the shiverer mutation. These results uncover an unsuspected axon to myelin traffic of Theiler's virus and the essential role played by the infection of myelin/oligodendrocyte in persistence. Theiler's virus persists in the central nervous system of mice and causes a chronic disease that resembles multiple sclerosis, a common demyelinating disease of humans. The virus infects neurons for one to two weeks, but later on it persists in the white matter, in oligodendrocytes and also in macrophages. Oligodendrocytes are the myelin-making cells of the central nervous system. Strikingly, in mice with a genetic defect of myelin, the virus infects neurons normally but is unable to persist. Understanding the reason for the lack of persistence in this mutant mouse should pinpoint an essential step in the complex process resulting in persistence. In this article, we show that resistance to persistent infection is not mediated by the immune system and is not due to inefficient viral replication in oligodendrocytes or macrophages. Instead, we show that virus transported in axons traffics into the myelin, and that this traffic is interrupted by the myelin mutation. This unsuspected axon to myelin traffic of Theiler's virus is necessary for viral persistence. Our results warrant looking for a similar phenomenon in other persistent infections of the nervous system, including in humans.
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影响因子：
3.2
作者：
Jackson, Alan C.;Rossiter, John P.;Lafon, Monique
通讯作者：
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DOI：
10.1073/pnas.0602460103
发表时间：
2006-05-16
影响因子：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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