Modulation of acyl-carnitines, the broad mechanism behind <i>Wolbachia</i>-mediated inhibition of medically important flaviviruses in <i>Aedes aegypti</i>.

Abstract

<i>Wolbachia</i>-infected mosquitoes are refractory to flavivirus infections, but the role of lipids in <i>Wolbachia</i>-mediated virus blocking remains to be elucidated. Here, we use liquid chromatography mass spectrometry to provide a comprehensive picture of the lipidome of <i>Aedes aegypti (Aag2)</i> cells infected with <i>Wolbachia</i> only, either dengue or Zika virus only, and <i>Wolbachia</i>-infected <i>Aag2</i> cells superinfected with either dengue or Zika virus. This approach identifies a class of lipids, acyl-carnitines, as being down-regulated during <i>Wolbachia</i> infection. Furthermore, treatment with an acyl-carnitine inhibitor assigns a crucial role for acyl-carnitines in the replication of dengue and Zika viruses. In contrast, depletion of acyl-carnitines increases <i>Wolbachia</i> density while addition of commercially available acyl-carnitines impairs <i>Wolbachia</i> production. Finally, we show an increase in flavivirus infection of <i>Wolbachia</i>-infected cells with the addition of acyl-carnitines. This study uncovers a previously unknown role for acyl-carnitines in this tripartite interaction that suggests an important and broad mechanism that underpins <i>Wolbachia</i>-mediated pathogen blocking.