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.