Recombinant Canine Distemper Virus Strain Snyder Hill Expressing Green or Red Fluorescent Proteins Causes Meningoencephalitis in the Ferret
Recombinant Canine Distemper Virus Strain Snyder Hill Expressing Green or Red Fluorescent Proteins Causes Meningoencephalitis in the Ferret
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DOI：
10.1128/jvi.06725-11
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发表时间：
2012-07-01
影响因子：
5.4
通讯作者：
Duprex, W. P.
中科院分区：
文献类型：
--
作者：
Ludlow, M.;Nguyen, D. T.;Duprex, W. P.
犬瘟热病毒(CDV)向中枢神经系统扩散的倾向是犬瘟热的主要特征之一。因此，我们开发了一种基于CDV神经毒株Snyder Hill(SH)株(CDVSH)的反向遗传学系统，并表明该病毒能够迅速绕过血脑和血脑脊液(CSF)屏障扩散到蛛网膜下腔，从而引发戏剧性的病毒性脑膜脑炎。利用表达增强型绿色荧光蛋白(EGFP)或红色荧光蛋白(DTomato)的重组CDVSH(rCDV(SH))有助于对病毒在体内传播途径的敏感病理评估。感染这些病毒的雪貂在大约2周的快速、致命的病程中会出现典型的与犬瘟热有关的全部临床症状。与雪貂适应的CDV5804P和原型野生型CDVR252的比较表明，脉络丛血源性感染不是病毒进入脑脊液的重要途径。相反，在感染rCDV(SH)的动物中，病毒传播到蛛网膜下腔是由血管内皮细胞感染和病毒感染的白细胞从脑膜血管向蛛网膜下腔的血源性扩散所触发的。这导致软脑膜的软脑膜和蛛网膜层的细胞广泛感染大脑半球的大片区域。CDV神经毒株在体内传播的灵敏评估为研究病毒进入脑脊液的机制和急性病毒性脑膜炎的发病机制提供了一种新的模型系统。
The propensity of canine distemper virus (CDV) to spread to the central nervous system is one of the primary features of distemper. Therefore, we developed a reverse genetics system based on the neurovirulent Snyder Hill (SH) strain of CDV (CDVSH) and show that this virus rapidly circumvents the blood-brain and blood-cerebrospinal fluid (CSF) barriers to spread into the subarachnoid space to induce dramatic viral meningoencephalitis. The use of recombinant CDVSH (rCDV(SH)) expressing enhanced green fluorescent protein (EGFP) or red fluorescent protein (dTomato) facilitated the sensitive pathological assessment of routes of virus spread in vivo. Infection of ferrets with these viruses led to the full spectrum of clinical signs typically associated with distemper in dogs during a rapid, fatal disease course of approximately 2 weeks. Comparison with the ferret-adapted CDV5804P and the prototypic wild-type CDVR252 showed that hematogenous infection of the choroid plexus is not a significant route of virus spread into the CSF. Instead, viral spread into the subarachnoid space in rCDV(SH)-infected animals was triggered by infection of vascular endothelial cells and the hematogenous spread of virus-infected leukocytes from meningeal blood vessels into the subarachnoid space. This resulted in widespread infection of cells of the pia and arachnoid mater of the leptomeninges over large areas of the cerebral hemispheres. The ability to sensitively assess the in vivo spread of a neurovirulent strain of CDV provides a novel model system to study the mechanisms of virus spread into the CSF and the pathogenesis of acute viral meningitis.