Coxsackievirus B3 and the neonatal CNS - The roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease
Coxsackievirus B3 and the neonatal CNS - The roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease
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DOI：
10.1016/s0002-9440(10)63496-7
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发表时间：
2003-10-01
影响因子：
6
通讯作者：
Whitton, JL
中科院分区：
文献类型：
--
作者：
Feuer, R;Mena, I;Whitton, JL
新生儿特别容易受到柯萨奇病毒感染的中枢神经系统（CNS），这可能会导致脑膜炎，脑炎和长期的神经功能缺损。然而，病毒在中枢神经系统中的嗜性和传播机制尚未研究。在这里，我们调查柯萨奇病毒B3（CVB 3）的嗜性和病理学在新生小鼠的中枢神经系统，使用重组病毒表达增强型绿色荧光蛋白（eGFP）。新生幼鼠极易受到柯萨奇病毒CNS感染，并且这种易感性在7日龄时显著降低。新生小鼠颅内感染后24小时，在脉络丛、嗅球和脑室内边缘的细胞中检测到病毒基因组RNA和病毒蛋白表达。许多受感染的细胞具有B型干细胞的解剖学特征，可以产生神经元和星形胶质细胞，并表达中间丝蛋白巢蛋白，这是祖细胞的标志物。随着感染的进展，在脑实质中鉴定出病毒蛋白，首先在表达神经元特异性III类β-微管蛋白（神经元分化的早期标志物）的细胞中，随后在表达NeuN（成熟神经元的标志物）的细胞中。在随后的时间点，病毒蛋白表达仅限于大脑特定区域的神经元，包括海马、内嗅和颞叶皮质以及嗅球。广泛的神经元死亡是可见的，似乎是由于病毒诱导的细胞凋亡。我们认为新生儿CNS对CVB感染的易感性增加可能是由病毒靶向新生儿干细胞解释的; CVB通过发育中的神经元进入脑实质，尽管感染，神经元仍继续迁移和分化。在完全成熟时，部分或全部受感染的神经元发生凋亡，由此产生的神经元损失可以解释长期的临床表现。
Neonates are particularly susceptible to coxsackievirus infections of the central nervous system (CNS), which can cause meningitis, encephalitis, and long-term neurological deficits. However, viral tropism and mechanism of spread in the CNS have not been examined. Here we investigate coxsackievirus B3 (CVB3) tropism and pathology in the CNS of neonatal mice, using a recombinant virus expressing the enhanced green fluorescent protein (eGFP). Newborn pups were extremely vulnerable to coxsackievirus CNS infection, and this susceptibility decreased dramatically by 7 days of age. Twenty-four hours after intracranial infection of newborn mice, viral genomic RNA and viral protein expression were detected in the choroid plexus, the olfactory bulb, and in cells bordering the cerebral ventricles. Many of the infected cells bore the anatomical characteristics of type B stem cells, which can give rise to neurons and astrocytes, and expressed the intermediate filament protein nestin, a marker for progenitor cells. As the infection progressed, viral protein was identified in the brain parenchyma, first in cells expressing neuron-specific class III beta-tubulin, an early marker of neuronal differentiation, and subsequently in cells expressing NeuN, a marker of mature neurons. At later time points, viral protein expression was restricted to neurons in specific regions of the brain, including the hippocampus, the entorhinal and temporal cortex, and the olfactory bulb. Extensive neuronal death was visible, and appeared to result from virus-induced apoptosis. We propose that the increased susceptibility of the neonatal CNS to CVB infection may be explained by the virus' targeting neonatal stem cells; and that CVB is carried into the brain parenchyma by developing neurons, which continue to migrate and differentiate despite the infection. On full maturation, some or all of the infected neurons undergo apoptosis, and the resulting neuronal loss can explain the longer-term clinical picture.