BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul 08308, Korea.
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
Cells. 2020 Nov 16;9(11):2487. doi: 10.3390/cells9112487.
Zika virus (ZIKV) remains as a public health threat due to the congenital birth defects the virus causes following infection of pregnant women. Congenital microcephaly is among the neurodevelopmental disorders the virus can cause in newborns, and this defect has been associated with ZIKV-mediated cytopathic effects in human neural progenitor cells (hNPCs). In this study, we investigated the cellular changes that occur in hNPCs in response to ZIKV (African and Asian lineages)-induced cytopathic effects. Transmission electron microscopy showed the progress of cell death as well as the formation of numerous vacuoles in the cytoplasm of ZIKV-infected hNPCs. Infection with both African and Asian lineages of ZIKV induced apoptosis, as demonstrated by the increased activation of caspase 3/7, 8, and 9. Increased levels of proinflammatory cytokines and chemokines (IL-6, IL-8, IL-1β) were also detected in ZIKV-infected hNPCs, while z-VAD-fmk-induced inhibition of cell death suppressed ZIKV-mediated cytokine production in a dose-dependent manner. ZIKV-infected hNPCs also displayed significantly elevated gene expression levels of the pro-apoptotic Bcl2-mediated family, in particular, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, TRAIL signaling led to augmented ZIKV-mediated cell death and the knockdown of TRAIL-mediated signaling adaptor, FADD, resulted in enhanced ZIKV replication. In conclusion, our findings provide cellular insights into the cytopathic effects induced by ZIKV infection of hNPCs.
寨卡病毒（ZIKV）仍然是一个公共卫生威胁，因为孕妇感染该病毒后会导致先天性出生缺陷。先天性小头畸形是该病毒在新生儿中引起的神经发育障碍之一，这种缺陷与寨卡病毒介导的人神经祖细胞（hNPCs）的细胞病变效应有关。在这项研究中，我们研究了 hNPCs 对寨卡病毒（非洲和亚洲谱系）诱导的细胞病变效应的反应中发生的细胞变化。透射电子显微镜显示了细胞死亡的进展以及寨卡病毒感染的 hNPCs 细胞质中形成的许多空泡。感染非洲和亚洲谱系的寨卡病毒都会诱导细胞凋亡，这表现为 caspase 3/7、8 和 9 的激活增加。在寨卡病毒感染的 hNPCs 中还检测到促炎细胞因子和趋化因子（IL-6、IL-8、IL-1β）水平升高，而 z-VAD-fmk 诱导的细胞死亡抑制以剂量依赖的方式抑制了寨卡病毒介导的细胞因子产生。寨卡病毒感染的 hNPCs 还显示出促凋亡 Bcl2 介导家族的基因表达水平显著升高，特别是肿瘤坏死因子相关凋亡诱导配体（TRAIL）。此外，TRAIL 信号导致增强的寨卡病毒介导的细胞死亡，并且 TRAIL 介导的信号衔接子 FADD 的敲低导致增强的寨卡病毒复制。总之，我们的研究结果提供了寨卡病毒感染 hNPCs 引起的细胞病变效应的细胞见解。
