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.

怀孕期间感染寨卡病毒 (ZIKV) 会导致胎儿出现一系列严重异常，称为先天性寨卡综合症 (CZS)。动物模型和体外系统的实验极大地促进了我们对 ZIKV 感染病理生理学的理解。在这里，为了研究人类 CZS 的分子基础，我们使用系统生物学方法整合来自 CZS 新生儿死后大脑的转录组学、蛋白质组学和基因组数据。我们观察到胶原蛋白在 RNA 和蛋白质水平的 CZS 大脑中的表达大大减少，并且患有 CZS 的新生儿在与成骨不全和关节弯曲相关的胶原蛋白编码基因中有几个单核苷酸多态性。这些发现通过免疫组织化学和 ZIKV 感染和未感染样本中胶原丰度的比较分析得到验证。此外，我们还发现 ZIKV 依赖性细胞粘附因子的表达增加，这些因子对轴突生长和轴突引导至关重要，这些发现与 CZS 中观察到的神经元迁移缺陷一致。总之，这些发现提供了对 ZIKV 感染大脑中潜在分子改变的见解，并揭示了与 CZS 易感性相关的宿主基因。