LC-MS/MS - NS-NE - Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons

Growing evidences have associated Zika virus infection with congenital malformations, including microcephaly. Nonetheless, signaling mechanisms that promote the disease outcome are far from being understood, affecting the development of suitable therapeutics. In this study, we applied shotgun mass spectrometry-based proteomics combined with cell biology approaches to characterize altered molecular pathways on neurons and NPCs infected by ZIKV-BR, strain obtained from the 2015 Brazilian outbreak. Assessment of neurons differentiated from iPSC from different donors shows the importance of the host genetic background to the susceptibility of ZIKV infection, also confirmed by cytokine fingerprinting. Additionally, infected cells presented an impairment of neurogenesis and synaptogenesis processes. Moreover, ZIKV-BR infected NPCs showed unique alteration of pathways involved in neurological diseases, cell death and survival and embryonic development compared to ZIKV-AF, showing a human adaptation of the Brazilian viral strain. Taken together, these data explain CNS developmental arrest observed in Congenital Zika Virus syndrome is beyond neuronal cell death.

越来越多的证据表明，寨卡病毒（Zika virus）感染可引发包括小头畸形（microcephaly）在内的多种先天性畸形。然而，调控该疾病进程的信号通路机制仍未完全阐明，这极大阻碍了针对性治疗策略的开发。本研究采用基于鸟枪法质谱的蛋白质组学（shotgun mass spectrometry-based proteomics）结合细胞生物学手段，对感染了ZIKV-BR毒株（分离自2015年巴西暴发疫情）的神经元与神经前体细胞（neural progenitor cells, NPCs）中发生异常调控的分子通路开展表征分析。对不同供体诱导多能干细胞（induced pluripotent stem cells, iPSC）分化所得神经元的评估结果显示，宿主遗传背景对寨卡病毒感染易感性具有重要影响，该结论经细胞因子指纹图谱分析得到了验证。此外，受病毒感染的细胞表现出神经发生与突触发生过程的功能受损。进一步对比发现，与ZIKV-AF毒株感染组相比，ZIKV-BR感染的神经前体细胞出现了涉及神经系统疾病、细胞存亡与胚胎发育的特有通路异常，提示该巴西病毒毒株已产生人类适应性进化。综合上述结果，本研究数据表明，先天性寨卡病毒综合征（Congenital Zika Virus syndrome）中观察到的中枢神经系统（central nervous system, CNS）发育停滞，其致病机制并非仅由神经元细胞死亡所介导。