由于据报道，在巴西感染ZIKV的孕妇的胎儿中，小头畸形是一致的结果，最近涉及寨卡病毒（ZIKV）-小头症的病因机制关系。研究人员,然而,仍在努力为这个有趣的因果手铐建立胚胎学基础。本研究揭示了有力的证据，有利于合理的ZIKV-小头症因果关系联系。基本原理基于：（1）ZIKV基因组与人类DNA中早期神经管发育标记“视黄酸”的反应元件之间的序列同源性，以及（2）ZIKV-小头畸形和视黄酸胚胎病的脑缺陷细节之间的全面相似性。视黄酸被认为是通过视黄酸依赖性基因启动子区的视黄酸反应元件（RARE）共有序列（5'-AGGTCA-3'）调节神经管前后轴和发育中脑结构定位的最早因子。我们筛选了已经报道的毒力ZIKV毒株（包括与小头畸形相关的毒株）和美国国立卫生研究院遗传序列数据库（GenBank）中的其他病毒的RARE共有重复序列，并获得了有力支持我们的假设的结果，即与小头畸形相关的ZIKV毒株可以通过在发育中的脑细胞基因组中引入额外的RARE共有序列重复序列来沉淀视黄酸依赖性基因调控异常。对我们假设的其他支持来自我们的发现，即筛选其他病毒的RARE共有序列重复仅对那些已知表现出神经嗜性并导致胎儿脑缺陷（可能需要在发育阶段进行母胎传播）的病毒是阳性的。RARE序列重复的数量似乎与筛选的阳性病毒的毒力相匹配。虽然,生物信息学证据和胚胎学特征支持我们的假设，包括动物模型在内的其他研究需要验证我们的主张.此类研究可能会揭示ZIKV-小头畸形的关联，并可能有助于设计与之对抗的方法。
Owing to the reports of
microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)-microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker \"retinoic acid\" in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE)
consensus sequence (5\'-AGGTCA-3\') in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE
consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE
consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE
consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.
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