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).