Lipid Interactions Between Flaviviruses and Mosquito Vectors

Abstract

Mosquito-borne flaviviruses, such as dengue (DENV), Zika (ZIKV), yellow fever (YFV), West Nile (WNV), and Japanese encephalitis (JEV) viruses, threaten a large part of the human populations. In absence of therapeutics and effective vaccines against each flaviviruses, targeting viral metabolic requirements in mosquitoes may hold the key to new intervention strategies. Development of metabolomics in the last decade opened a new field of research: mosquito metabolomics. It is now clear that flaviviruses rely on mosquito lipids, especially phospholipids, for their cellular cycle and propagation. Here, we review the biosyntheses of, biochemical properties of and flaviviral interactions with mosquito phospholipids. Phospholipids are structural lipids with a polar headgroup and apolar acyl chains, enabling the formation of lipid bilayer that form plasma- and endomembranes. Phospholipids are mostly synthesized through the de novo pathway and remodeling cycle. Variations in headgroup and acyl chains influence phospholipid physicochemical properties and consequently the membrane behavior. Flaviviruses interact with cellular membranes at every step of their cellular cycle. Recent evidence demonstrates that flaviviruses reconfigure the phospholipidome in mosquitoes by regulating phospholipid syntheses to increase virus multiplication. Identifying the phospholipids involved and understanding how flaviviruses regulate these in mosquitoes is required to design new interventions.

Evidence of Differences in Cellular Regulation of Wolbachia-Mediated Viral Inhibition between Alphaviruses and Flaviviruses

“…Further studies have shown that unlike flaviviruses, which actively increase cholesterol biosynthesis, alphaviruses seem to lead to a decrease in cholesterol biosynthesis: suggesting key differences in their requirement for cholesterol [ 31 , 32 , 33 ]. Alphaviruses also utilise host cell membranes, namely plasma membranes, in order to form replication complexes, unlike flaviviruses which are known to utilise ER membranes [ 31 , 34 ]. The lipid composition of ER membranes compared to plasma membranes is fundamentally different, and therefore, the effect of Wolbachia on the availability of cholesterol at each of these membranes is also likely to be different [ 35 ].…”

The influence of the larval microbiome on susceptibility to Zika virus is mosquito genotype dependent

“…Additionally, recent research has shed light on the critical role of nutrition in determining the outcome of infection in mosquitoes. In particular, lipid metabolism plays a crucial role in the replication and dissemination of arboviruses within the mosquito's body [50][51][52][53][54][55], while amino acids are involved in the mosquito's interaction with the microbiome [45,56]. Given that the mosquito's nutritional status is strongly influences by its microbiome, and that the nutritional status of the mosquito can influence arbovirus infection, it is not surprising that we observe significant variation in the rates of ZIKV infection when mosquitoes are reared in different bacterial communities.…”

Profiling lipidomic changes in dengue-resistant and dengue-susceptible strains of Colombian Aedes aegypti after dengue virus challenge

“…In our study, the GLs that were most significantly dysregulated in Cali-MIB+DENV samples were DAGs, TAGs, PC, PE, and PG. These lipids are intricately related; DAG can be converted to PC or PE as membrane components, or the production of TAGs for energy storage [ 60 , 61 ]. Interestingly, TAGs are primarily stored within the cytoplasm in lipid droplets, which are surrounded by a monolayer of amphipathic phospholipids, mainly of PC and PE [ 61 ].…”