3.3.1 JEV regulation of apoptosis
Although the pathogenic mechanism of JEV is similar to that of WNV, JEV
manipulates both intrinsic and extrinsic pathways to its advantage. The
replication of JEV triggers a variety of cell apoptosis, as confirmed by
DNA fragmentation ladder, nuclear condensation and TUNEL
assay(C. L. Liao et al., 1997), and the
stable expression of human Bcl-2 can delay JEV-induced
apoptosis(C. L. Liao et al., 1998).
Although JEV induces the classic intrinsic apoptotic pathway in N18
neuroblastoma cells, it activates both caspase-8 (part of the extrinsic
pathway) and caspase-9 in a predominantly mitochondria-dependent pathway
in MCF cells(Tsao et al., 2008). The
regulation of JEV and its protein on apoptosis is summarized in Table 3.
Further, the apoptotic cell death induced by JEV depends on ER stress
and the generation of ROS. Current research shows that these three
proteins GRP78, mitochondrial protein
Prohibitin (PHB), and
heterogeneous nuclear ribonucleoprotein (hnRNPC) interact with JEV RNA,
which in turn causes ER stress-induced
apoptosis(Mukherjee et al., 2017).
Another result shows that JEV-induced ER stress participates in the
apoptosis process through p38-dependent and CHOP-mediated
pathways(Hong-Lin, Ching-Len, & Yi-Ling,
2002; Sankar, Utsav, & Sudhanshu,
2014), and the IRE1/JNK pathway of ER stress is also an important
mechanism for JEV to induce apoptosis(M.
Huang et al., 2016). Even replication-incompetent strain (UV-JEV)
retain their ability to kill neuronal cells by triggering a
ROS-dependent, partly NF-κB-mediated
pathway(R.-J. Lin, Liao, & Lin, 2004).
In addition, Guo et al.(Guo et al., 2018)
found that JEV induces apoptosis by inhibiting the STAT3-Foxo-Bcl-6/p21
pathway, indicating that this pathway has a certain pro-survival effect,
which provides novel insights into JEV-induced encephalitis. Followed,
significant up-regulation of Bax, Bid, Fas , FasL and down-regulation of
IGFBP-2, p27, p53 were respectively observed in JEV infected cells with
0.5 and 10 MOI compared to uninfected
cells(Al-Obaidi et al., 2017). As a
result, in the case of low MOI, expression of proteins involved in
inducing apoptosis indicates that the immune system has played a
protective role of in preventing the virus from completing its
replication and producing infectious progeny viruses. While at high MOI,
most of proapoptotic proteins are reduced, which means that the virus
has capacity to disable host cell apoptotic mechanisms that may be
obligatory for virus life cycle completion.