Pro-apoptosis
Autopsy of fatal DHF/DSS cases caused by DENV2 demonstrated apoptotic cells in liver, brain, intestinal and lung tissues, and the apoptotic microvascular endothelial cells (ECs) in intestinal and pulmonary tissues explain the patient’s plasma leakage(Limonta, Capó, Torres, Pérez, & Guzmán, 2007). DENV2 infection of human ECs leads to up-regulation of IL-8 (interleukin-8) and RANTES (regulated upon activation normal T cell expressed and secreted factor), these cytokines accumulate at serosal sites and cause local vascular leakage, which has been observed to accompany apoptosis(Avirutnan, Malasit, Seliger, Bhakdi, & Husmann, 1998). Further research found that DENV2 induces ECs apoptosis through XIAP-associated factor 1 (XAF1)-dependent pathway, XAF1 is one of the interferon-inducing genes, it upregulates caspase-3 36 h after infection and mediates cell apoptosis(Junqi Huang et al., 2014; Long et al., 2013).
Besides, the intrinsic apoptotic pathway also plays an important role in this context. In HepG2 cells, DENV2 promoted changes in mitochondrial bioenergetics and caused typical apoptotic morphological changes, including cytoplasmic contraction, mitochondrial swelling and plasma membrane blistering(El-Bacha et al., 2007). In fact, changes in mitochondrial promote the activation of caspase-9, which then activates caspase-3, leading to DNA cleavage and apoptosis(Suwanmanee & Luplertlop, 2017; Torrentes-Carvalho et al., 2009). Further results showed that in HepG2 cells, DENV2 initiated the unfolded protein response and the Noxa/PUMA stress response pathways(Thepparit et al., 2013). Moreover, a series of protein phosphorylation reactions are essential for inducing cell apoptosis. For example, DENV2 (strain 16881) increases the phosphorylation of JNK1/2 and p38MAPK through both intrinsic and extrinsic apoptotic pathways, leading to liver injury. The induced p53 phosphorylation and the decrease of anti-apoptotic Bcl-2 expression indicate the involvement of intrinsic apoptotic pathway, in which the induced expression of TNF-α and TRAIL may participate in the extrinsic apoptotic pathway(Sreekanth et al., 2017).
In addition, DENV2 can activate the transcription factor NF-κB, NF-κB translocates to the nucleus to activate pro-inflammatory cytokine TNF-α, and TNF-α binds to its transmembrane receptor TNFR to activate caspase-8 and dowmstrem effector caspase-3(Amar et al., 2011; Netsawang et al., 2014). Similarly, FasL interacts with Fas receptor present on immune cells to trigger apoptosis signals(H. Liao, Xu, & Huang, 2010). In the TNF-α and FasL signaling pathways, the activation of enzyme phospholipase A2 (PLA2) seems to be essential for inducing apoptosis(Jäättelä, Benedict, Tewari, Shayman, & Dixit, 1995; Nevalainen & Losacker, 1997). This enzyme converts membrane phospholipids into arachidonic acid (AA), which is the main lipid mediator of several intracellular reactions(Axelrod, Burch, & Jelsema, 1988; Malewicz, Parthasarathy, Jenkin, & Baumann, 1981). AA stimulates the synthesis of NADPH oxidase to produce superoxide anions and other reactive oxygen species (ROS)(Jan et al., 2000), ROS can act as signal transducers and activate the expression of genes involved in apoptosis like NF-κB(Xiao & Ghosh, 2005). As well, excessive ROS will eventually initiate the mitochondrial apoptosis pathway(Olagnier et al., 2014). Moreover, a positive correlation between apoptosis, DNA damage and oxidative stress was found in PBMCs infected with DENV2, which paved the way for the determination of plausible immunopathological links contributing to disease pathogenesis. Besides, secondary messenger oxides like nitric oxide (NO) also mediates dengue-triggered apoptosis in a caspase dependent manner(C.-F. Lin et al., 2002). Beyond that, functional studies have shown that knocking down the sphingosine kinase2 (SPHK2) in HUH-7 cells infected with four serotypes of DENV reduce the activities of caspase-9 and caspase-3, suggesting that SPHK2 plays a role in promoting apoptosis through intrinsic pathway(A Morchang et al., 2017).