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).