Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected.
Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected.
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DOI：
10.1186/s40478-017-0450-8
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发表时间：
2017-06-23
影响因子：
7.1
通讯作者：
Edgar JM
中科院分区：
文献类型：
--
作者：
Cumberworth SL;Barrie JA;Cunningham ME;de Figueiredo DPG;Schultz V;Wilder-Smith AJ;Brennan B;Pena LJ;Freitas de Oliveira França R;Linington C;Barnett SC;Willison HJ;Kohl A;Edgar JM
最近全球爆发的寨卡病毒（ZIKV）感染与影响外周和中枢神经系统（分别为PNS和CNS）的严重神经系统疾病有关。这些不同临床表型背后的病理生物学是深入研究的主题;然而，即使是易受生产性寨卡病毒感染的主要神经细胞类型也仍然缺乏特征。在这里，我们使用来自野生型和Ifnar 1基因敲除小鼠的CNS和PNS髓鞘形成培养物来检查神经元和神经胶质的向性以及ZIKV巴西变体直接感染的短期后果。细胞培养物在髓鞘形成前或髓鞘形成后感染不同的时间间隔，然后用细胞类型和ZIKV特异性抗体染色。在使用离体培养绕过全身免疫和Ifnar 1缺陷细胞中的I型干扰素应答中，我们能够评估神经细胞的内在感染性。通过髓鞘形成培养物中ZIKV感染细胞的系统定量，我们发现ZIKV感染在不存在I型干扰素应答的情况下增强，并且CNS细胞比PNS细胞对感染显著更敏感。特别是，我们证明，中枢神经系统轴突和髓鞘少突胶质细胞是特别容易受到伤害。这些结果对于理解与ZIKV感染相关的神经症状的病理生物学具有意义。此外，我们提供了一个可量化的离体感染模型，可用于病毒神经侵袭及其后果的基础和治疗研究。本文的在线版本（doi：10.1186/s40478-017-0450-8）包含补充材料，可供授权用户使用。
The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). The pathobiology underlying these diverse clinical phenotypes are the subject of intense research; however, even the principal neural cell types vulnerable to productive Zika infection remain poorly characterised. Here we used CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV. Cell cultures were infected pre- or post-myelination for various intervals, then stained with cell-type and ZIKV-specific antibodies. In bypassing systemic immunity using ex vivo culture, and the type I interferon response in Ifnar1 deficient cells, we were able to evaluate the intrinsic infectivity of neural cells. Through systematic quantification of ZIKV infected cells in myelinating cultures, we found that ZIKV infection is enhanced in the absence of the type I interferon responses and that CNS cells are considerably more susceptible to infection than PNS cells. In particular, we demonstrate that CNS axons and myelinating oligodendrocytes are especially vulnerable to injury. These results have implications for understanding the pathobiology of neurological symptoms associated with ZIKV infection. Furthermore, we provide a quantifiable ex vivo infection model that can be used for fundamental and therapeutic studies on viral neuroinvasion and its consequences. The online version of this article (doi:10.1186/s40478-017-0450-8) contains supplementary material, which is available to authorized users.