Cain Matthew D, Salimi Hamid, Gong Yongfeng, Yang Lihua, Hamilton Samantha L, Heffernan James R, Hou Jianghui, Miller Mark J, Klein Robyn S
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, United States.
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, United States.
J Neuroimmunol. 2017 Jul 15;308:118-130. doi: 10.1016/j.jneuroim.2017.04.008. Epub 2017 May 1.
Viral infections of the central nervous system (CNS) are often associated with blood-brain barrier (BBB) disruption, yet the impact of virus replication and immune cell recruitment on BBB integrity are incompletely understood. Using two-photon microscopy, we demonstrate that Venezuelan equine encephalitis virus (VEEV) strain TC83-GFP, a GFP expressing, attenuated strain with a G3A mutation within the 5' UTR that is associated with increased sensitivity to type I interferons (IFNs), does not directly impact BBB permeability. Following intranasal infection of both wild-type and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1)-deficient mice, which fail to block TC83-specific RNA translation, virus spreads to the olfactory bulb and cortex via migration along axonal tracts of neurons originating from the olfactory neuroepithelium. Global dissemination of virus in the CNS by 2days post-infection (dpi) was associated with increased BBB permeability in the olfactory bulb, but not in the cortex or hindbrain, where permeability only increased after the recruitment of CX3CR1 and CCR2 mononuclear cells on 6 dpi, which corresponded with tight junction loss and claudin 5 redistribution. Importantly, despite higher levels of viral replication, similar results were obtained in IFIT1-deficient mice. These findings indicate that TC83 gains CNS access via anterograde axonal migration without directly altering BBB function and that mononuclear and endothelial cell interactions may underlie BBB disruption during alphavirus encephalitis.
中枢神经系统（CNS）的病毒感染通常与血脑屏障（BBB）破坏有关，但病毒复制和免疫细胞募集对BBB完整性的影响尚未完全了解。使用双光子显微镜，我们证明委内瑞拉马脑炎病毒（VEEV）株TC83-GFP，一种表达GFP的减毒株，在5'UTR内具有G3A突变，与对I型干扰素（IFN）的敏感性增加有关，不会直接影响BBB通透性。在野生型和缺乏四肽重复序列1（IFIT1）的IFN诱导蛋白的小鼠鼻内感染后，这些小鼠无法阻断TC83特异性RNA翻译，病毒通过沿着源自嗅神经上皮的神经元轴突束迁移扩散到嗅球和皮质。感染后2天（dpi）病毒在中枢神经系统中的全身扩散与嗅球中BBB通透性增加有关，但在皮质或后脑则不然，在6 dpi时CX3CR1和CCR2单核细胞募集后通透性才增加，这与紧密连接丧失和claudin 5重新分布相对应。重要的是，尽管病毒复制水平较高，但在IFIT1缺陷小鼠中也获得了类似结果。这些发现表明，TC83通过顺行轴突迁移进入中枢神经系统，而不会直接改变BBB功能，并且单核细胞与内皮细胞的相互作用可能是甲病毒脑炎期间BBB破坏的基础。
