The Role of Tissue Oxygen Tension in Dengue Virus Replication.

Efseveia Frakolaki,Panagiotis Liakos,Katerina Kalliampakou,Maria Moraiti,Ralf Bartenschlager,Eleni Dotsika,Panagiota Kaimou,Penelope Mavromara,Niki Vassilaki,Dido Vassilacopoulou,Kalliopi Karampetsou

doi:10.3390/cells7120241

Abstract

Low oxygen tension exerts a profound effect on the replication of several DNA and RNA viruses. In vitro propagation of Dengue virus (DENV) has been conventionally studied under atmospheric oxygen levels despite that in vivo, the tissue microenvironment is hypoxic. Here, we compared the efficiency of DENV replication in liver cells, monocytes, and epithelial cells under hypoxic and normoxic conditions, investigated the ability of DENV to induce a hypoxia response and metabolic reprogramming and determined the underlying molecular mechanism. In DENV-infected cells, hypoxia had no effect on virus entry and RNA translation, but enhanced RNA replication. Overexpression and silencing approaches as well as chemical inhibition and energy substrate exchanging experiments showed that hypoxia-mediated enhancement of DENV replication depends on the activation of the key metabolic regulators hypoxia-inducible factors 1α/2α (HIF-1α/2α) and the serine/threonine kinase AKT. Enhanced RNA replication correlates directly with an increase in anaerobic glycolysis producing elevated ATP levels. Additionally, DENV activates HIF and anaerobic glycolysis markers. Finally, reactive oxygen species were shown to contribute, at least in part through HIF, both to the hypoxia-mediated increase of DENV replication and to virus-induced hypoxic reprogramming. These suggest that DENV manipulates hypoxia response and oxygen-dependent metabolic reprogramming for efficient viral replication.

Highlights

The dengue virus (DENV) is an important mosquito-borne member of the Flavivirus genus in the Flaviviridae family, causing widely distributed and endemic, visceral, and central nervous system diseases [1]
We found that reactive oxygen species (ROS) induction by hypoxia-mediated Dengue virus (DENV) replication increase, as well as DENV-induced ROS under normoxic conditions contributed to hypoxia inducible factors (HIF) activation (Figure 8)
Based on the previously reported link between ROS and HIF-1α stabilization [62,64], which was confirmed in our studies (Figure S5), we propose that the positive role of hypoxia-induced ROS in viral replication might be mediated, at least in part, by HIF

Summary

Introduction

The dengue virus (DENV) is an important mosquito-borne member of the Flavivirus genus in the Flaviviridae family, causing widely distributed and endemic, visceral, and central nervous system diseases [1]. Cells 2018, 7, 241; doi:10.3390/cells7120241 www.mdpi.com/journal/cells (dengue fever) to the more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [2]. Secondary heterotypic infection is a risk factor to develop DHF/DSS, mediated most likely by antibody-dependent enhancement of infection (ADE) [3]. The global incidence of dengue has grown dramatically in recent decades [4,5,6]. The recently approved dengue vaccine has only limited overall efficacy [7]. There is no approved antiviral therapy [8]

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Discussion

Conclusion