Anti-apoptosis
Although DENV2 has the function of inducing cell apoptosis, it also has
the function of inhibiting cell apoptosis. Pena and
Harris(José & Eva, 2011) demonstrated
that DENV2 manipulates the sequence of events to activate and inhibit
the three different branches of UPR in a time-dependent manner, so that
cells can adapt to infection stress, overcome translational inhibition,
prevent premature apoptosis, and ultimately extend the life cycle of the
virus. For instance, inhibition of XBP1 combined with DENV2 infection
can lead to weakened ER expansion, enhanced cytopathic effects of the
virus and increased levels of the apoptosis marker
procaspase-3(C.-Y. Yu, Hsu, Liao, & Lin,
2006). This further proves that the IRE1-XBP1 pathway can protect cells
from apoptosis and reduce ER stress contributing to DENV pathogenesis,
similar results have been observed in JEV-infected cells. Moreover, in
mosquito cells, DENV-2 infection causes UPR to activate the PERK
signaling pathway, thereby reducing the accumulation of ER stress, and
activating anti-apoptotic effects to help cells survive the continuous
amplification of the virus(Hou et al.,
2017). This phenomenon is very important for elucidating how mosquitoes
can healthily serve as carriers of DENV and may-be other arboviruses.
Another result showed that all the capsid proteins from 6 different
flaviviruses (DENV, JEV, WNV, YFV, MVEV and SLEV) confer a protective
effect on Fas-dependent apoptosis in a manner that increases
phosphorylation of Akt thereby enhancing cell
activity(Hart & Vogt, 2011). Moreover,
protein phosphatase 1, which is known to inactivate Akt, was identified
as a DENV-C interacting protein, indicating that DENV-C activates Akt by
sequestering phosphatases that downregulate
phosphor-Akt(Airo et al., 2018).
Meanwhile, some factors play a role in inhibiting apoptosis in the
process of DENV infection. DENV2-infected cells express high levels of
calcium modulating
cyclophilin-binding ligand (CMAL), a regulator of intracellular calcium
levels(Bram & Crabtree, 1994), the cells
therefore have high cytosolic calcium concentration, which can help
DENV2 to subvert apoptosis since it protects cells from mitochondrial
damage(J. Li et al., 2012). Bcl-xL also
plays a vital role in the survival of DENV, JEV and ZIKV infected cells,
therefore Bcl-xL provides a novel antiviral target for inhibiting the
propagation of flavivirus(Suzuki et al.,
2018).