Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome
Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome
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DOI：
10.1126/scisignal.aay6736
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发表时间：
2020-06-09
影响因子：
7.3
通讯作者：
Nakaya, Helder, I
中科院分区：
文献类型：
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作者：
Aguiar, Renato S.;Pohl, Fabio;Nakaya, Helder, I
寨卡病毒（ZIKV）是一种常见的寨卡病毒性传染病，它会导致胎儿出现一系列严重的畸形，称为先天性寨卡综合征（CZS）。动物模型和体外系统的实验大大有助于我们理解ZIKV感染的病理生理学。在这里，研究人类CZS的分子基础，我们使用了系统生物学方法整合转录组，蛋白质组学和基因组数据与CZS新生儿死后的大脑。我们观察到胶原蛋白在CZS脑中的表达在RNA和蛋白质水平上都大大降低，并且患有CZS的新生儿在胶原蛋白编码基因中有几个单核苷酸多态性，这些基因与成骨不全和关节弯曲相关。这些发现通过免疫组织化学和ZIKV感染和未感染样品中胶原蛋白丰度的比较分析来验证。此外，我们显示了ZIKV依赖性的细胞粘附因子表达的增加，这些细胞粘附因子对于神经突生长和轴突引导是必不可少的，这一发现与在CZS中观察到的神经元迁移缺陷一致。总之，这些发现为ZIKV感染的大脑中潜在的分子改变提供了见解，并揭示了与CZS易感性相关的宿主基因。
Zika virus (ZIKV) infection during pregnancy can cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS). Experiments with animal models and in vitro systems have substantially contributed to our understanding of the pathophysiology of ZIKV infection. Here, to investigate the molecular basis of CZS in humans, we used a systems biology approach to integrate transcriptomic, proteomic, and genomic data from the postmortem brains of neonates with CZS. We observed that collagens were greatly reduced in expression in CZS brains at both the RNA and protein levels and that neonates with CZS had several single-nucleotide polymorphisms in collagen-encoding genes that are associated with osteogenesis imperfecta and arthrogryposis. These findings were validated by immunohistochemistry and comparative analysis of collagen abundance in ZIKV-infected and uninfected samples. In addition, we showed a ZIKV-dependent increase in the expression of cell adhesion factors that are essential for neurite outgrowth and axon guidance, findings that are consistent with the neuronal migration defects observed in CZS. Together, these findings provide insights into the underlying molecular alterations in the ZIKV-infected brain and reveal host genes associated with CZS susceptibility.