Regulation of autophagy, glucose uptake, and glycolysis under dengue virus infection

Abstract

We previously reported that dengue virus (DENV)-induced autophagy plays a promoting role in viral replication and pathogenesis both in vitro and in vivo. Although it is known that DENV infection increases glycolysis, which promotes viral replication, the role of glucose metabolism together with autophagic activity in DENV replication remains unclear. In this study, we reveal that DENV2 infection increased autophagic activity, glucose uptake, protein levels of glucose transporter-1 (GLUT1), and glycolysis rate-limiting enzyme hexokinase-2 (HK2) in cells. Furthermore, the protein levels of LC3-II and HK2 were increased in the brain tissues of the DENV2-infected suckling mice. However, DENV2 infection decreased ATP level and showed no effect on mRNA expression of HK2 and phosphofructokinase, as well as lactate production, indicating that DENV2-regulated glycolytic flux occurs at the post-transcriptional level and is lactate pathway-independent. Moreover, amiodarone-induced autophagic activity, glucose uptake, HK2 level, and viral titer were reversed by the autophagy inhibitor spautin-1 or silencing of Atg5 gene expression. Intriguingly, blocking of glycolysis, HK2 protein level, and viral titer were accordingly decreased, but autophagic activity was increased, suggesting the existence of another regulation mechanism that influences the relationship between glycolysis and autophagy. This is the first report to reveal that DENV2-induced autophagy positively regulates glycolysis and viral replication in vitro and in vivo. Our findings open a new avenue wherein metabolic modulation could be used as a target for the treatment of DENV infection.

Keywords: autophagy; dengue virus; glucose uptake; glycolysis.