A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS.
A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS.
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DOI：
10.1523/jneurosci.1860-10.2010
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发表时间：
2010-06-23
期刊：
影响因子：
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通讯作者：
Feuer R
中科院分区：
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作者：
Tabor-Godwin JM;Ruller CM;Bagalso N;An N;Pagarigan RR;Harkins S;Gilbert PE;Kiosses WB;Gude NA;Cornell CT;Doran KS;Sussman MA;Whitton JL;Feuer R
新生儿肠道病毒感染是引起无菌性脑膜炎和脑炎的重要原因。使用新生小鼠模型，我们先前确定，柯萨奇B3病毒（CVB 3）优先目标位于脑室下区的神经干细胞增殖感染后24小时内。在稍后的时间点，未成熟的成神经细胞和最终成熟的神经元被感染，如通过高水平的病毒蛋白表达所确定的。在这里，我们表明，血液来源的Mac 3+单核细胞迅速招募到中枢神经系统后12小时内颅内感染CVB 3。这些细胞显示出骨髓样形态，基于GFP标记的过继细胞移植检查是外周来源的，并且在它们迁移到中枢神经系统（CNS）期间对CVB 3感染高度敏感。系列免疫荧光图像表明，髓样细胞通过脉络丛进入中枢神经系统，并且它们可能在外渗和通过脉络丛上皮期间被感染;这些感染的髓样细胞最终渗透到脑实质中。在它们通过室管膜细胞层（ECL）迁移之前，这些感染的髓样细胞的亚群表达可检测水平的巢蛋白（神经干细胞和祖细胞的标记物）。当这些被CVB 3感染的巢蛋白+髓样细胞迁移通过ECL时，它们显示出B型神经干细胞典型的独特形态学特征。这些新的骨髓细胞的募集可以通过在CVB 3感染后非常早期诱导的CNS中诱导独特的趋化因子谱而特异性地启动，其包括CCL 12的上调。我们认为颅内CVB 3感染可能导致巢蛋白+髓样细胞进入CNS，这可能代表了宿主固有的CNS修复反应。反过来，募集的骨髓细胞的增殖和代谢状态可能使它们成为CVB 3感染的有吸引力的靶标。此外，这些骨髓细胞的迁移能力可能指向病毒在CNS内传播的一种有效方法。
Enterovirus infection in newborn infants is a significant cause of aseptic meningitis and encephalitis. Using a neonatal mouse model, we previously determined that coxsackievirus B3 (CVB3) preferentially targets proliferating neural stem cells located in the subventricular zone within 24 hours after infection. At later time points, immature neuroblasts, and eventually mature neurons, were infected as determined by expression of high levels of viral protein. Here, we show that blood-derived Mac3+ mononuclear cells were rapidly recruited to the CNS within 12 hours after intracranial infection with CVB3. These cells displayed a myeloid-like morphology, were of a peripheral origin based on GFP-tagged adoptive cell transplant examination, and were highly susceptible to CVB3 infection during their migration into the central nervous system (CNS). Serial immunofluorescence images suggested that the myeloid cells enter the CNS via the choroid plexus, and that they may be infected during their extravasation and passage through the choroid plexus epithelium; these infected myeloid cells ultimately penetrate into the parenchyma of the brain. Prior to their migration through the ependymal cell layer (ECL), a subset of these infected myeloid cells expressed detectable levels of nestin, a marker for neural stem and progenitor cells. As these nestin+ myeloid cells infected with CVB3 migrated through the ECL, they revealed distinct morphological characteristics typical of type B neural stem cells. The recruitment of these novel myeloid cells may be specifically set in motion by the induction of a unique chemokine profile in the CNS induced very early after CVB3 infection, which includes upregulation of CCL12. We propose that intracranial CVB3 infection may lead to the recruitment of nestin+ myeloid cells into the CNS which might represent an intrinsic host CNS repair response. In turn, the proliferative and metabolic status of recruited myeloid cells may render them attractive targets for CVB3 infection. Moreover, the migratory ability of these myeloid cells may point to a productive method of virus dissemination within the CNS.