Lipidomics identifies a requirement for peroxisomal function during influenza virus replication

Influenza virus acquires a host-derived lipid envelope during budding, yet a convergent view on the role of host lipid metabolism during infection is lacking. Using a mass spectrometry-based lipidomics approach, we provide a systems-scale perspective on membrane lipid dynamics of infected human lung epithelial cells and purified influenza virions. We reveal enrichment of the minor peroxisome-derived ether-linked phosphatidylcholines relative to bulk ester-linked phosphatidylcholines in virions as a unique pathogenicity-dependent signature for influenza not found in other enveloped viruses. Strikingly, pharmacological and genetic interference with peroxisomal and ether lipid metabolism impaired influenza virus production. Further integration of our lipidomics results with published genomics and proteomics data corroborated altered peroxisomal lipid metabolism as a hallmark of influenza virus infection in vitro and in vivo. Influenza virus may therefore tailor peroxisomal and particularly ether lipid metabolism for efficient replication.