The Role of Tissue Oxygen Tension in Dengue Virus Replication

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.

Contribution of hypoxia inducible factor-1 during viral infections

“…Interestingly, the hypoxia-mediated enhancement of DENV replication was facilitated by HIF-1α/2α and by the serine/threonine kinase AKT, correlating with increased anaerobic glycolysis. Reactive oxygen species contributed to the hypoxia-mediated increase in DENV replication and to virus-induced hypoxic reprogramming [ 94 ] Figure 3 .…”

Andrographolide and Its 14-Aryloxy Analogues Inhibit Zika and Dengue Virus Infection

“…Hsp70 and Ran were identified to interact with JEV NS5, and knockdown of Hsp70 by the short-hairpin RNA (shRNA) corresponding to the HSPA1A mRNA sequences resulted in a significantly reduced JEV genome replication [39]. It is reported in vitro that DENV activates hypoxia inducible factor (HIF) and anaerobic glycolysis markers and enhanced DENV RNA replication correlates directly with an increase in anaerobic glycolysis, producing elevated adenosine triphosphate (ATP levels) [40]. As PGK1 and TKT are involved in energy metabolism, it is worth noting that TKT links the pentose phosphate pathway and the glycolysis pathway and active glycolysis has been shown to be required for DENV infection [41].…”

Virome Temporal Variation During Sea Star Wasting Disease Progression in Pisaster ochraceus (Asteroidea, Echinodermata)

“…Additionally, SSWD susceptibility correlates with morphological features which influence surface boundary layer extent and respiratory demand compared to theoretical diffusion, which taken together are evidence that wasting is associated with suboxic conditions at the animal-water interface [8]. O2 tension in cells triggers production of many viruses [66]. For example, flaviviruses and nucleocytoplasmic large DNA viruses use hypoxia inducible factors (HIF; genetic switches and genes that activate under hypoxic conditions), to stimulate production [67][68][69][70][71][72].…”