3.4.1 ZIKV regulation of apoptosis
It is worth noting that ZIKV infection can induce apoptosis through caspase-3-mediated pathways both in vitro and in vivo (J. Chen et al., 2017; W.-C. Huang, Abraham, Shim, Choe, & Page, 2016; M.-Y. Lin et al., 2017; Yan et al., 2019). Further, a variety of apoptosis markers were detected in neural parenchyma isolated from clinical cases, including FASL, FAS, Bax and caspase-3(de Sousa et al., 2018). And numerous reports show that neural cell apoptosis increases after ZIKV infection(Ghouzzi et al., 2017; W.-C. Huang et al., 2016; C. Li et al., 2016; Qian et al., 2016; Souza et al., 2016). For example, ZIKV preferentially induces apoptosis of neuro progenitor cells (NPCs), which is confirmed by the activation of caspases-3/7, -8 and -9, as well as ultrastructural and flow cytometry analysis(Jungmann, Pires, & Araujo Júnior, 2017; Martinot et al., 2018; Tang et al., 2016). In human neural stem cells (hNSCs), the cleavage of PARP and caspase-3 are participated in the apoptosis process(Devhare, Meyer, Steele, Ray, & Ray, 2017). These results contribute to ZIKV-induced abnormal development of the nervous system. The regulation of ZIKV and its protein on apoptosis is summarized in Table 4.
In addition to neural cells, many other cell types can also cause extensive apoptosis after ZIKV infection, such as HEK293 (embryonic cells)(H. Liu et al., 2019), GSCs (glioma stem cells)(Q. Chen et al., 2018), Vero and A549(McFadden et al., 2018; Park et al., 2019) (epithelial cells) and hepatocyte cells lines (HuH7.5 and HepG2)(Sherman et al., 2019). Another result suggests that ZIKV induces renal apoptosis by down-regulating expression of Bcl-2 and the up-regulating the expression of cleaved caspase-3 and PARP(T. Liu et al., 2019), which is similar to that observed in neural cells. Interestingly, ZIKV infection is related to pro-inflammatory cytokine expression and apoptosis in placental explants, thus we propose that human placental explants can be used as a model for studying ZIKV infection in vitro (Ribeiro et al., 2018).
The tumor suppressor protein p53 is also involved in ZIKV-mediated apoptosis, as the inhibition of p53 limits ZIKV-induced apoptosis in neural progenitors(Zhang et al., 2016). Since p53 can activate several pro-apoptotic genes such as Bax, Noxa and Puma, and inhibit anti-apoptotic gene survivin, leading to the activation of apoptosis. The physiological and metabolic changes in the ER after ZIKV infection lead to the activation of ER stress, and continuous ER stress then triggers apoptosis via upregulation of CHOPin vivo (Gladwyn-Ng et al., 2018; Oyarzún-Arrau, Alonso-Palomares, Valiente-Echeverría, Osorio, & Soto-Rifo, 2020; Tan et al., 2018).