3.2.1 WNV regulation of apoptosis
Although West Nile virus is not as versatile as dengue, it can trigger central nervous system (CNS) cell apoptosis, therefore establishing neuroinvasiveness. Neuro⁃2a cells (neuronal cells) and K562 (immune cells) infected by WNV show typical apoptotic characteristics, and the up-regulated Bax gene is involved(Parquet, Kumatori, Hasebe, Morita, & Igarashi, 2001). Furthermore, WNV infection can induce T98G cells (brain-derived) death through extrinsic and intrinsic apoptotic pathways, and caspase-3 dependent apoptosis contributes to the pathogenesis of fetal WNV encephalitis(Bimmi, David, & Diamond, 2003; Kleinschmidt, Michaelis, Ogbomo, Doerr, & Cinatl, 2007; Peng & Wang, 2019; Samuel, Morrey, & Diamond, 2007), which helps to clarify the pathogenesis of WNV-induced neuronal cell death and propose novel therapeutic targets that may restrict CNS damage. In Vero cells (epithelial cells), WNV can trigger the mitochondrial-mediated apoptosis pathway at low infectious doses (MOI<10), which is initiated by the release of Cyt-c and the formation of apoptosome. In contrast, cells infected with a higher load (MOI>10) showed signs of necrosis(Chu & Ng, 2003). The regulation of WNV and its protein on apoptosis is summarized in Table 2.
The ER stress is also involved, Medigeshi et al.(Medigeshi et al., 2007) found that the activation of two branches of UPR (ATF6 and PERK) after WNV infection can induce the production of proapoptotic CHOP and downstream apoptosis. However, WNVKUN (Kunjun strain) closes PERK pathway while activates the remaining two UPR (ATF6, IRE1) pathways in MEFs, further studies have found that these pathways increase cell viability and viral load by restricting apoptotic cell death(Ambrose & Mackenzie, 2013). Surprisingly, after the WNV vector mosquitoes Culex pipiens pipiens (C.p.pipiens ) are infected with WNV, a large number of midgut epithelial cells undergo apoptosis, which may affect virus transmission, disease epidemiology and viral evolution(Vaidyanathan & Scott, 2006). Furthermore, in human and mouse cell culture, WNV affects non-coding microRNAs (miRNAs), among which microRNA Hs_154 is significantly upregulated. Two of its targets, CTCF (CCCTC-binding factor) and ECOP (EGFR-coamplified and overexpressed protein) are related to cell survival(Smith, Grey, Uhrlaub, Janko, & Hirsch, 2012). The observation suggests that induction of Hs_154 expression can promote cell apoptosis, so this miRNA may become a candidate for therapeutic intervention.