van den Pol Anthony N, Mao Guochao, Yang Yang, Ornaghi Sara, Davis John N
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520.
J Neurosci. 2017 Feb 22;37(8):2161-2175. doi: 10.1523/JNEUROSCI.3124-16.2017. Epub 2017 Jan 25.
Zika virus (ZIKV), a positive-sense RNA flavivirus, has attracted considerable attention recently for its potential to cause serious neurological problems, including microcephaly, cortical thinning, and blindness during early development. Recent findings suggest that ZIKV infection of the brain can occur not only during very early stages of development, but also in later fetal/early neonatal stages of maturation. Surprisingly, after peripheral inoculation of immunocompetent mice on the day of birth, the first cells targeted throughout the brain were isolated astrocytes. At later stages, more neurons showed ZIKV immunoreactivity, in part potentially due to ZIKV release from infected astrocytes. In all developing mice studied, we detected infection of retinal neurons; in many mice, this was also associated with infection of the lateral geniculate, suprachiasmatic nuclei, and superior colliculus, suggesting a commonality for the virus to infect cells of the visual system. Interestingly, in mature mice lacking a Type 1 interferon response (IFNR), after inoculation of the eye, the initial majority of infected cells in the visual system were glial cells along the optic tract. ZIKV microinjection into the somatosensory cortex on one side of the normal mouse brain resulted in mirror infection restricted to the contralateral somatosensory cortex without any infection of midline brain regions, indicating the virus can move by axonal transport to synaptically coupled brain loci. These data support the view that ZIKV shows considerable complexity in targeting the CNS and may target different cells at different stages of brain development. Zika virus (ZIKV) can cause substantial damage to the developing human brain. Here we examine a developmental mouse model of ZIKV infection in the newborn mouse in which the brain is developmentally similar to a second-trimester human fetus. After peripheral inoculation, the virus entered the CNS in all mice tested and initially targeted astrocytes throughout the brain. Infections of the retina were detected in all mice, and infection of CNS visual system nuclei in the brain was common. We find that ZIKV can be transported axonally, thereby enhancing virus spread within the brain. These data suggest that ZIKV infects multiple cell types within the brain and that astrocyte infection may play a more important role in initial infection than previously appreciated.
寨卡病毒（ZIKV）是一种正义单链RNA黄病毒，最近因其在早期发育过程中可能导致严重神经问题（包括小头畸形、皮质变薄和失明）而备受关注。最近的研究结果表明，寨卡病毒对大脑的感染不仅可能发生在发育的极早期阶段，也可能发生在胎儿后期/新生儿早期成熟阶段。令人惊讶的是，在出生当天对免疫功能正常的小鼠进行外周接种后，整个大脑中首个被靶向的细胞是分离的星形胶质细胞。在后期阶段，更多神经元显示出寨卡病毒免疫反应性，部分原因可能是寨卡病毒从受感染的星形胶质细胞中释放出来。在所有研究的发育中小鼠中，我们检测到视网膜神经元感染；在许多小鼠中，这也与外侧膝状体、视交叉上核和上丘的感染有关，这表明该病毒感染视觉系统细胞具有共性。有趣的是，在缺乏1型干扰素反应（IFNR）的成熟小鼠中，接种眼睛后，视觉系统中最初大多数受感染细胞是沿视束的神经胶质细胞。将寨卡病毒微量注射到正常小鼠大脑一侧的体感皮层会导致镜像感染局限于对侧体感皮层，而中线脑区无任何感染，这表明该病毒可通过轴突运输转移到突触连接的脑区。这些数据支持这样一种观点，即寨卡病毒在靶向中枢神经系统方面表现出相当大的复杂性，并且可能在大脑发育的不同阶段靶向不同的细胞。寨卡病毒（ZIKV）可对发育中的人类大脑造成严重损害。在此，我们研究了新生小鼠寨卡病毒感染的发育小鼠模型，其中小鼠大脑在发育上类似于妊娠中期的人类胎儿。外周接种后，病毒在所有测试小鼠中进入中枢神经系统，最初靶向整个大脑的星形胶质细胞。在所有小鼠中均检测到视网膜感染，并且大脑中枢神经系统视觉系统核团感染很常见。我们发现寨卡病毒可通过轴突运输，从而增强病毒在脑内的传播。这些数据表明，寨卡病毒感染大脑内多种细胞类型，并且星形胶质细胞感染在初始感染中可能比以前认为的发挥更重要的作用。
