Figure 2.

Host metabolic pathways are necessary for DENV replication: As an enveloped virus, DENV requires fatty acids for replication and virion envelopment, resulting in virus-mediated modifications in the host cellular systems. These modifications lead to alterations in glucose and glutamine metabolism, as well as fatty acid synthesis. At the primary level of infection, lipid droplets and nucleotides are reabsorbed into the endoplasmic reticulum (ER) and subsequently assemble with the DENV virus. Glucose uptake in DENV-infected cells may increase through the induction of the glucose transporter 4 (GLUT-4) or overexpression of glucose transporter 1 (GLUT-1) and hexokinase II (HK-II), the first enzyme of glycolysis. DENV infection alters glucose metabolism allosterically by up-regulation of glycolytic enzymes. Infected cells stimulate glycolysis to produce ATP through the tricarboxylic acid (TCA) cycle. It also generates citrate, which is a precursor of fatty acid biosynthesis. Glucose carbons are diverted and subsequently migrate to the cytoplasm from the TCA cycle through citrate. Exogenous glutamine uptake is increased in DENV-infected cells [5]. The TCA cycle is maintained by glutaminolysis enzymes that are induced by DENV, whereas imported glutamine was converted into α-ketoglutarate. Fatty acid and sterol synthesis are upregulated, so that acetyl-coenzyme A (AcCoA) can be used for fatty acid synthesis. Lipid synthetic enzymes are modified to generate a large amount of distinct membrane lipid [60,61]. Experimentally limiting glucose and fatty acid synthesis during DENV infection, along with limiting glutamine levels, can help prevent infections.