Type II interferon signaling in the brain during a viral infection with age-dependent pathogenesis.
Type II interferon signaling in the brain during a viral infection with age-dependent pathogenesis.
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DOI：
10.1002/dneu.22778
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发表时间：
2020-07
影响因子：
3
通讯作者：
O'Donnell LA
中科院分区：
文献类型：
--
作者：
Creisher PS;Chandwani MN;Kamte YS;Covvey JR;Ganesan P;O'Donnell LA
中枢神经系统（CNS）的病毒感染通常以年龄依赖性方式引起疾病，在胎儿和新生儿时期神经病理学更严重。转基因 CD46+ 小鼠通过中枢神经系统神经元的麻疹病毒感染来模拟这些年龄依赖性结果。成年 CD46+ 小鼠以干扰素γ (IFNγ) 依赖性方式控制病毒传播并在感染中存活，而新生 CD46+ 小鼠尽管大脑中存在类似的 IFNγ 表达，但仍会死亡。因此，我们假设成人大脑中的 IFNγ 信号传导可能更加强大，这可能是由于 IFNγ 信号蛋白的基础表达更高。为了检验这一假设，我们评估了在没有感染的情况下新生儿和成人大脑中典型 IFNγ 信号蛋白的表达，包括 IFNγ 受体、Janus 激酶 (JAK) 1/2 以及信号转导器和转录激活剂 1 (STAT1)。我们还分析了 MV 感染期间 STAT1 和 IFNγ 刺激基因的表达和激活。我们发现新生儿大脑的海马体和小脑中的 JAK/STAT1 表达与成人相同或更高。 IFNγ受体的表达因大脑中的细胞类型而异，但在神经元和神经胶质细胞上广泛表达。在 MV 感染期间，无论年龄如何，STAT1 表达和激活的增加与海马中的病毒载量相关，但与小脑中的病毒载量无关，而小脑中的病毒载量在成人中始终检测不到。这些结果表明，新生儿大脑能够在病毒感染期间启动 IFNγ 信号传导，但下游 STAT1 激活不足以限制病毒传播。
Viral infections of the central nervous system (CNS) often cause disease in an age-dependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)-dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription-1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ-stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.
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影响因子：
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作者：
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10.1016/j.bbrc.2015.08.104
发表时间：
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