Flavivirus modulation of cellular metabolism

Abstract

Over the last decade, we have begun to appreciate how flaviviruses manipulate cellular metabolism to establish an optimal environment for their replication. These metabolic changes include the stimulation of glycolysis, in addition to lipid anabolic and catabolic pathways. These processes are thought to promote an energetically favorable state, in addition to modifying membrane lipid composition for viral replication and virion envelopment. Importantly, many of these processes can be pharmacologically inhibited as successful antiviral strategies, at least in cell culture. In this review, we discuss the mechanisms by which flaviviruses alter cellular metabolism, remaining questions, and opportunities for therapeutic development.

Serum lipid profile as a predictor of dengue severity: A systematic review and meta‐analysis

“…The interpretation of clinical and laboratory data for the characterization of the severity of dengue disease is rather complex; however, recent studies have pointed out the value of circulating lipids as potential biomarkers. Targeting this biomacromolecule has gained appeal for its prognostic value for dengue because both in vivo and in vitro studies have shown that the DENV modulates lipid metabolism to enable the virus to infect host cells . In this study, we have summarized the current knowledge on the prognostic value of lipid levels in patients with dengue, and we have evaluated how different variables influence this association through meta‐analysis and subgroup assessment.…”

“…Biochemically, it is known that infection by DENV alters some components associated with triglyceride metabolism. During the multiplication phase, NS3 protein from DENV increases the activity of FASN, a rate‐limiting enzyme in triglycerides biosynthesis, in human cells . Perera and collaborators have demonstrated that the activation of FASN occurs also in mosquito cells, showing that the triglycerides have an emerging role in shaping the membrane and protein environments during viral infections of vector .…”

“…The broad variation in responses to DENV infection among individuals makes it difficult to identify markers of severity. One strategy is to evaluate changes in metabolite levels, and this approach has revealed that DENV changes lipid metabolism during its life cycle in the host cell . To escape the innate immune response, provide a physical scaffold on which the viruses can assemble and replicate, and increase the local concentration of cofactors required for replication, DENV forms organelles in the endoplasmic reticulum known as replication complexes (RCs) that require fatty acids, cholesterol, and phospholipids.…”

“…To escape the innate immune response, provide a physical scaffold on which the viruses can assemble and replicate, and increase the local concentration of cofactors required for replication, DENV forms organelles in the endoplasmic reticulum known as replication complexes (RCs) that require fatty acids, cholesterol, and phospholipids. To achieve this, viral proteins (especially nonstructural protein 3—NS3) sequester the fatty acid synthase (FASN) and 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase (HMGCR) to the RC, resulting in increased cholesterol uptake and synthesis of triacylglycerol after viral infection . DENV was also recently related to regulate the degradation of the host lipid droplet; it has been shown that a viral protein (NS4A) exploits the acyltransferase activity of AUP1, a lipid droplet‐localized type‐III membrane protein, to trigger lipophagy .…”

Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

“…Recent advances have revealed that positive-stranded RNA viruses, including the flaviviruses, rearrange host cell lipid metabolism and coopt for cellular lipids to com-plete their life cycle (5)(6)(7). Considering this dependence on lipid metabolism during flavivirus infection, pharmacological modification of the lipid metabolic pathways appears to be a proper strategy to impair flaviviral replication (7,8).…”