Mosquito metabolomics reveal that dengue virus replication requires phospholipid reconfiguration via the remodeling cycle

Abstract

Dengue virus (DENV) subdues cell membranes for its cellular cycle by reconfiguring phospholipids in humans and mosquitoes. Here, we determined how and why DENV reconfigures phospholipids in the mosquito vector. By inhibiting and activating the de novo phospholipid biosynthesis, we demonstrated the antiviral impact of de novo–produced phospholipids. In line with the virus hijacking lipids for its benefit, metabolomics analyses indicated that DENV actively inhibited the de novo phospholipid pathway and instead triggered phospholipid remodeling. We demonstrated the early induction of remodeling during infection by using isotope tracing in mosquito cells. We then confirmed in mosquitoes the antiviral impact of de novo phospholipids by supplementing infectious blood meals with a de novo phospholipid precursor. Eventually, we determined that phospholipid reconfiguration was required for viral genome replication but not for the other steps of the virus cellular cycle. Overall, we now propose that DENV reconfigures phospholipids through the remodeling cycle to modify the endomembrane and facilitate formation of the replication complex. Furthermore, our study identified de novo phospholipid precursor as a blood determinant of DENV human-to-mosquito transmission.

Mosquito-bacteria interactions during larval development trigger metabolic changes with carry-over effects on adult fitness

“…The link between lipid metabolism and DENV infection in Ae. aegypti was highlighted in several recent studies [44][45][46] and supports the hypothesis that the observed carry-over effects on DENV vector competence also derive from remodeling of lipid metabolism.…”

Unraveling mosquito metabolism with mass spectrometry-based metabolomics

“…These studies suggest that the dengue virus modulates mosquito metabolism for its own benefit [53,54]. In agreement with these findings, recent nontargeted LC/MS metabolomics and stable-label isotope tracing analyses indicate that the dengue virus inhibits the de novo PL pathway and actively reconfigures PLs through the remodeling cycle in mosquito vector to facilitate its replication [55]. It was also found that ethanolamine, a blood metabolite, reduces mosquito infection and serves as a de novo PL precursor and as a determinant of human-to-mosquito virus transmission [55].…”

Lipid Interactions Between Flaviviruses and Mosquito Vectors

“…Recent studies, including ours, showed that DENV perturb lipid composition in Aedes cell lines, midguts, and whole mosquitoes (Perera et al, 2012;Chotiwan et al, 2018;Vial et al, 2019Vial et al, , 2020. Unfortunately, to our knowledge there is no study with other flavivirus species in mosquitoes.…”

“…There is a negative crosstalk between de novo PL biogenesis and PL remodeling, whereby activation of one inhibits the other. Previous observation that de novo PL production is inactivated by DENV suggests that PL remodeling is induced by infection (Figure 9; Vial et al, 2020). To demonstrate activation of PL remodeling, we developed isotope tracing of PL in mosquito cells.…”

“…Several lines of evidence indicate that de novo PLs are not favorable to virus multiplication ( Figure 9 and Table 1 ). We have shown that inhibition of several enzymes involved in de novo PL biogenesis promotes DENV infection in mosquito cells ( Vial et al, 2020 ). Likewise, we showed that depletion of AGPAT1 enzyme involved in the synthesis of PA, the precursor for all de novo PLs, increased virus load ( Vial et al, 2019 ).…”