Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly
Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly
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DOI：
10.1038/s41593-017-0038-4
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发表时间：
2018-01-01
影响因子：
25
通讯作者：
Nguyen, Laurent
中科院分区：
文献类型：
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作者：
Gladwyn-Ng, Ivan;Cordon-Barris, Lluis;Nguyen, Laurent
越来越多的证据支持妊娠期寨卡病毒（ZIKV）感染与先天性小头畸形之间存在因果关系。然而，ZIKV相关小头畸形的机制仍不清楚。我们结合了对ZIKV感染的人类胎儿、培养的人类神经干细胞和小鼠胚胎的分析，以了解ZIKV如何诱导小头畸形。我们表明，ZIKV触发内质网应激和未折叠的蛋白质反应，在感染的死后人类胎儿的大脑皮层，以及在培养的人神经干细胞。在小鼠胚胎中脑内和胎盘内接种ZIKV后，我们表明它在体内引发胚胎脑中的内质网应激。这扰乱了皮质祖细胞内控制神经发生的生理性未折叠蛋白质反应。因此，ZIKV感染的祖细胞产生较少的投射神经元，其最终定居在大脑皮层中，因此持续的内质网应激导致细胞凋亡。此外，我们证明了未折叠蛋白反应的药理学抑制剂的施用抵消了这些病理生理学机制，并防止ZIKV感染的小鼠胚胎中的小头畸形。这样的缺陷对ZIKV是特异性的，因为在小鼠中胎盘内注射其他相关黄病毒后未观察到它们。
Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV-associated microcephaly remains unclear. We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice.