Zika virus infection of neural stem cells to model pathogen-induced microcephaly

寨卡病毒(ZIKV)是黄病毒属的一种RNA病毒，正在引起一种新的全球流行。ZIKV感染与神经疾病密切相关，包括先天性小头畸形，在先天性小头畸形中，大脑大小严重缩小。此外，疾控中心最近得出结论，ZIKV导致小头畸形症。ZIKV相关性小头畸形症的严重程度暗示着早期对大脑发育的侮辱。在人类小头症大脑中，ZIKV RNA已在神经元和未来的胶质细胞中被检测到。在ZIKV感染的小鼠模型中，也在这些相同的人群中检测到病毒。ZIKV还被证明可以感染神经干细胞，影响它们的生长和存活。在胎儿大脑发育的早期阶段，神经干细胞产生神经元，并随着发育的进行转移到胶质细胞的产生。神经干细胞功能障碍被认为是遗传性小头畸形的根本原因。总之，这表明了一种潜在的机制，可以解释为什么ZIKV同时感染神经元和神经胶质细胞。在这项提议中，我们将检验ZIKV感染以胚胎神经干细胞为目标的假设，改变它们的细胞行为和转录组。使用我们实验室开发的一套新的分析方法，我们将追求两个目标。首先，我们将确定ZIKV如何影响神经干细胞，包括产生新的可存活的后代。其次，我们将定义神经干细胞中受ZIKV感染动态调节的宿主mRNAs。完成后，这些目标将阐明对寨卡病毒生物学的基本了解，特别是在发育中的神经系统内，这是开始控制寨卡病毒流行的基本信息。

Zika virus (ZIKV) is an RNA virus of the flavivirus genus that is causing an emerging global epidemic. ZIKV infection has been strongly associated with neurological disorders, including congenital microcephaly, in which brain size is severely reduced. Moreover the CDC has recently concluded that ZIKV causes microcephaly. The severity of ZIKV-associated microcephaly is suggestive of an early insult to brain development. In human microcephalic brains, ZIKV RNA has been detected in neurons and prospective glia. In mouse models of ZIKV infection, virus has also been detected in these same populations. ZIKV has also been shown to infect neural stem cells impacting their growth and survival. During early stages of fetal brain development, neural stem cells produce neurons and shift to glia production as development proceeds. Neural stem cell dysfunction is thought to be an underlying cause for genetic forms of microcephaly. Altogether this suggests a potential mechanism to explain why ZIKV infects both neurons and glia. In this proposal we will test the hypothesis that ZIKV infection targets embryonic neural stem cells, altering their cellular behavior and transcriptome. Using a novel set of assays developed in our labs, we will pursue two aims. First, we will determine how ZIKV impacts neural stem cells including production of new viable progeny. Second we will define the host mRNAs dynamically regulated by ZIKV infection in neural stem cells. Upon completion, these aims will elucidate a fundamental understanding of ZIKV biology, particularly within the developing nervous system, essential information for beginning to control the ZIKV epidemic.