Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain.
Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain.
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DOI：
10.1186/s12974-016-0571-1
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发表时间：
2016-05-13
影响因子：
9.3
通讯作者：
O'Donnell LA
中科院分区：
文献类型：
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作者：
Fantetti KN;Gray EL;Ganesan P;Kulkarni A;O'Donnell LA
在发育中的大脑中，自我更新的神经干/祖细胞（NSPC）产生神经元和神经胶质谱系。嗜神经病毒和抗病毒免疫反应可以改变NSPC的存活和分化。几种嗜神经病毒特异性靶向并感染NSPCs，除了诱导神经元损失之外，这使得难以区分由于直接病毒感染或由于抗病毒免疫应答对NSPCs的影响。我们研究了麻疹病毒（MV）感染新生儿抗病毒免疫对NSPCs的影响。使用神经元限制性病毒感染模型，其中NSPCs保持未感染。因此，诱导了抗病毒免疫应答，而没有NSPC感染的混淆问题。使用了两种转基因小鼠品系：CD 46+小鼠在神经元特异性烯醇化酶启动子的控制下表达人CD 46亚型（MV进入受体）; CD 46 +/IFNγ-KO小鼠缺乏关键的抗病毒细胞因子IFNγ。使用多色流式细胞术和Western印迹分析分别定量对NSPC、神经元和神经胶质细胞数量的影响，并定量对IFNγ介导的信号传导和细胞标志物的影响。流式细胞术分析显示，在感染后3、7和10天（dpi），CD 46 +/IFNγ-KO小鼠中的NSPCs减少，但在CD 46+小鼠中不受影响。早期神经元在两种基因型中在7 dpi时表现出最大的细胞损失，对成熟神经元和神经胶质细胞没有影响。因此，IFNγ保护NSPC的损失，但不保护年轻的神经元。对海马外植体的Western印迹分析显示，在没有IFNγ的情况下巢蛋白表达减少，两种基因型中的doublecortin和β III-微管蛋白表达减少。在海马中，STAT 1和STAT 2的磷酸化独立于IFNγ发生，尽管具有不同的激活调节。这是第一项证明抗病毒免疫对NSPC功能的旁观者效应的研究。我们的研究结果表明IFNγ在新生儿病毒性CNS感染期间保护NSPC群体。CD 46 +/IFNγ-KO新生儿中NSPCs的显著损失表明，在不存在IFNγ的情况下，适应性免疫应答对NSPCs是有害的。这些结果揭示了抗病毒免疫应答对神经病理学的重要性和贡献，并且可能与其他神经炎症状况相关。本文的在线版本（doi：10.1186/s12974-016-0571-1）包含补充材料，可供授权用户使用。
In the developing brain, self-renewing neural stem/progenitor cells (NSPC) give rise to neuronal and glial lineages. NSPC survival and differentiation can be altered by neurotropic viruses and by the anti-viral immune response. Several neurotropic viruses specifically target and infect NSPCs, in addition to inducing neuronal loss, which makes it difficult to distinguish between effects on NSPCs that are due to direct viral infection or due to the anti-viral immune response. We have investigated the impact of anti-viral immunity on NSPCs in measles virus (MV)-infected neonates. A neuron-restricted viral infection model was used, where NSPCs remain uninfected. Thus, an anti-viral immune response was induced without the confounding issue of NSPC infection. Two-transgenic mouse lines were used: CD46+ mice express the human isoform of CD46, the MV entry receptor, under the control of the neuron-specific enolase promoter; CD46+/IFNγ-KO mice lack the key anti-viral cytokine IFNγ. Multi-color flow cytometry and Western Blot analysis were used to quantify effects on NSPC, neuronal, and glial cell number, and quantify effects on IFNγ-mediated signaling and cell markers, respectively. Flow cytometric analysis revealed that NSPCs were reduced in CD46+/IFNγ-KO mice at 3, 7, and 10 days post-infection (dpi), but were unaffected in CD46+ mice. Early neurons showed the greatest cell loss at 7 dpi in both genotypes, with no effect on mature neurons and glial cells. Thus, IFNγ protected against NSPC loss, but did not protect young neurons. Western Blot analyses on hippocampal explants showed reduced nestin expression in the absence of IFNγ, and reduced doublecortin and βIII-tubulin in both genotypes. Phosphorylation of STAT1 and STAT2 occurred independently of IFNγ in the hippocampus, albeit with distinct regulation of activation. This is the first study to demonstrate bystander effects of anti-viral immunity on NSPC function. Our results show IFNγ protects the NSPC population during a neonatal viral CNS infection. Significant loss of NSPCs in CD46+/IFNγ-KO neonates suggests that the adaptive immune response is detrimental to NSPCs in the absence of IFNγ. These results reveal the importance and contribution of the anti-viral immune response to neuropathology and may be relevant to other neuroinflammatory conditions. The online version of this article (doi:10.1186/s12974-016-0571-1) contains supplementary material, which is available to authorized users.