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).