@article{fdi:010079424,
  title = {{D}engue virus reduces {AGPAT}1 expression to alter phospholipids and enhance infection in {A}edes aegypti},
  author = {{V}ial, {T}homas and {T}an, {W}. {L}. and {X}iang, {B}. {W}. {W}. and {M}iss{\'e}, {D}oroth{\'e}e and {D}eharo, {E}ric and {M}arti, {G}. and {P}ompon, {J}ulien},
  editor = {},
  language = {{ENG}},
  abstract = {{A}uthor summary {D}engue is endemic in tropical and subtropical regions, and has now encroached onto temperate regions because of the geographic expansion of its vector, {A}edes aegypti. {I}n the absence of effective vaccine and curative drug, the sole intervention relies on containment strategies using insecticide. {H}owever, occurrence of insecticide resistance diminishes vector control efficacy. {H}ere, we explore the nascent field of mosquito metabolomics as part of our discovery effort for new transmission-blocking targets. {D}engue virus ({DENV}) relies on host metabolome, specifically the lipid membrane to complete its life-cycle. {H}owever, little is known about how {DENV} subverts the mosquito physiology. {U}sing high-resolution mass spectrometry, we described metabolic changes incurred by {DENV} throughout the mosquito cycle, from cellular replication onset to systemic infection. {M}embrane phospholipids were highly reconfigured and were associated with reduced expression of {AGPAT}1, an enzyme involved in their biogenesis. {AGPAT}1 depletion partially recapitulated {DENV}-induced metabolic reconfiguration and enhanced infection by maintaining high phospholipid concentrations. {T}hese phospholipids were then consumed/redirected later in the mosquito {DENV} cycle. {O}ur work comprehensively describes metabolic changes associated with {DENV} infection. {I}n addition, we reveal how {DENV} subdues the lipidome for its benefit by demonstrating the role of phospholipids in mosquito infection. {M}ore than half of the world population is at risk of dengue virus ({DENV}) infection because of the global distribution of its mosquito vectors. {DENV} is an envelope virus that relies on host lipid membranes for its life-cycle. {H}ere, we characterized how {DENV} hijacks the mosquito lipidome to identify targets for novel transmission-blocking interventions. {T}o describe metabolic changes throughout the mosquito {DENV} cycle, we deployed a {L}iquid chromatography-high resolution mass spectrometry ({LC}-{HRMS}) workflow including spectral similarity annotation in cells, midguts and whole mosquitoes at different times post infection. {W}e revealed a major aminophospholipid reconfiguration with an overall early increase, followed by a reduction later in the cycle. {W}e phylogenetically characterized acylglycerolphosphate acyltransferase ({AGPAT}) enzyme isoforms to identify those that catalyze a rate-limiting step in phospholipid biogenesis, the acylation of lysophosphatidate to phosphatidate. {W}e showed that {DENV} infection decreased {AGPAT}1, but did not alter {AGPAT}2 expression in cells, midguts and mosquitoes. {D}epletion of either {AGPAT}1 or {AGPAT}2 increased aminophospholipids and partially recapitulated {DENV}-induced reconfiguration before infection in vitro. {H}owever, only {AGPAT}1 depletion promoted infection by maintaining high aminophospholipid concentrations. {I}n mosquitoes, {AGPAT}1 depletion also partially recapitulated {DENV}-induced aminophospholipid increase before infection and enhanced infection by maintaining high aminophospholipid concentrations. {T}hese results indicate that {DENV} inhibition of {AGPAT}1 expression promotes infection by increasing aminophospholipids, as observed in the mosquito's early {DENV} cycle. {F}urthermore, in {AGPAT}1-depleted mosquitoes, we showed that enhanced infection was associated with increased consumption/redirection of aminophospholipids. {O}ur study suggests that {DENV} regulates aminophospholipids, especially phosphatidylcholine and phosphatidylethanolamine, by inhibiting {AGPAT}1 expression to increase aminophospholipid availability for virus multiplication.},
  keywords = {},
  booktitle = {},
  journal = {{PL}o{S} {P}athogens},
  volume = {15},
  numero = {12},
  pages = {e1008199 [23 p.]},
  ISSN = {1553-7366},
  year = {2019},
  DOI = {10.1371/journal.ppat.1008199},
  URL = {https://www.documentation.ird.fr/hor/fdi:010079424},
}