Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly ¹ and Guillain-Barré syndrome^2,3 as ZIKV-associated neurological complications. Recent reports have also indicated other neurological manifestations to be associated with ZIKV, including myelitis ⁴ , meningoencephalitis ⁵ and fatal encephalitis ⁶ . Here, we investigate the neuropathogenesis of ZIKV infection in type I interferon receptor IFNAR knockout (Ifnar1 ^-/- ) mice, an infection model that exhibits high viral burden within the central nervous system. We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1 deficiency in the haematopoietic compartment. However, spread of ZIKV within the central nervous system is supported by Ifnar1-deficient non-haematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8⁺ effector T cells. We also find that antiviral activity of CD8⁺ T cells within the brain markedly limits ZIKV infection of neurons, but, as a consequence, instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV neuropathogenesis within a susceptible mouse model and suggests blood-brain barrier breakdown and T-cell-mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

中文翻译：

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抗病毒CD8 T细胞在小鼠中诱发寨卡病毒相关的瘫痪。

寨卡病毒（ZIKV）是一种新兴的蚊媒RNA病毒。ZIKV在美洲的快速传播已经揭示了小头畸形¹和Guillain-Barré综合征^2,3作为ZIKV相关的神经系统并发症。最近的报道也表明与ZIKV相关的其他神经系统表现包括脊髓炎⁴，脑膜脑炎⁵和致命性脑炎⁶。在这里，我们调查了I型干扰素受体IFNAR基因敲除（Ifnar1 ^-/-）小鼠，一种在中枢神经系统内表现出高病毒负荷的感染模型。我们显示ZIKV从感染部位到大脑的系统性传播需要在造血区室中Ifnar1缺乏症。然而，Ifnar1缺陷型非造血细胞支持ZIKV在中枢神经系统内的扩散。在这种情况下，星形胶质细胞的ZIKV感染导致血脑屏障的破坏和CD8 ⁺效应T细胞的大量涌入。我们还发现CD8 ^+的抗病毒活性大脑中的T细胞显着限制了ZIKV对神经元的感染，但结果却加剧了ZIKV相关的瘫痪。综上所述，我们的研究揭示了易感小鼠模型中ZIKV神经发病机制的潜在机制，并提出血脑屏障破坏和T细胞介导的神经病理学是人类ZIKV相关神经系统并发症的潜在基础。