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.