Abstract
BackgroundDengue and Dengue hemorrhagic fever have emerged as some of the most important mosquito-borne viral diseases in the tropics. The mechanisms of pathogenesis of Dengue remain elusive. Recently, virus-induced apoptosis mediated by the Unfolded Protein Response (UPR) has been hypothesised to represent a crucial pathogenic event in viral infection. In an attempt to evaluate the contribution of the UPR to virus replication, we have characterized each component of this signalling pathway following Dengue virus infection.ResultsWe find that upon Dengue virus infection, A549 cells elicit an UPR which is observed at the level of translation attenuation (as visualized by the phosphorylation of eIF2alpha) and activation of specific pathways such as nuclear translocation of ATF-6 and splicing of XBP-1. Interestingly, we find that specific serotype of virus modulate the UPR with different selectivity. In addition, we demonstrate that perturbation of the UPR by preventing the dephosphorylation of the translation initiation factor eIF2alpha using Salubrinal considerably alters virus infectivity.ConclusionThis report provides evidence that Dengue infection induces and regulates the three branches of the UPR signaling cascades. This is a basis for our understanding of the viral regulation and conditions beneficial to the viral infection. Furthermore, modulators of UPR such as Salubrinal that inhibit Dengue replication may open up an avenue toward cell-protective agents that target the endoplasmic reticulum for anti-viral therapy.
Highlights
Dengue and Dengue hemorrhagic fever have emerged as some of the most important mosquito-borne viral diseases in the tropics
To determine whether eIF2α is phosphorylated upon Dengue infection, A549 cells were infected for 6 to 72 hours with DENV2 (TSV01) or DENV1 (MY 10245) viruses and harvested at indicated time points post-infection (Fig. 2)
This indicates that eIF2α kinases such as PERK or PKR are activated upon infection of A549 cells by Dengue virus
Summary
Dengue and Dengue hemorrhagic fever have emerged as some of the most important mosquito-borne viral diseases in the tropics. Virus-induced apoptosis mediated by the Unfolded Protein Response (UPR) has been hypothesised to represent a crucial pathogenic event in viral infection. In an attempt to evaluate the contribution of the UPR to virus replication, we have characterized each component of this signalling pathway following Dengue virus infection. Dengue is caused by four antigenically distinct viruses designated as Dengue virus type 1–4 (DENV 1–4) and is transmitted between vertebrate hosts by insect vectors. The genome is translated into a single polypeptide which is co- and post-translationally processed by host signalases as well as the virus encoded serine protease into the three structural and seven non structural proteins (NS) in the order C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4BNS5 that traverse the Endoplasmic Reticulum (ER) membrane (Fig. 1). We hypothesize that these events will lead to the activation of the ER stress response which in turn will modulate various signaling pathways resulting in cell survival or death decisions
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