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Dengue virus serotype infection specifies the activation of the unfolded protein response

Indira Umareddy1, Olivier Pluquet2, Qing Yin Wang1, Subhash G Vasudevan1, Eric Chevet2 and Feng Gu1*

Author Affiliations

1 Novartis Institute for Tropical Diseases, 10-Biopolis Road, #05-01 Chromos, 138670, Singapore

2 Team AVENIR, GREF INSERM U899, IFR66, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France

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Virology Journal 2007, 4:91  doi:10.1186/1743-422X-4-91

Published: 24 September 2007

Abstract

Background

Dengue 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.

Results

We 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.

Conclusion

This 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.