Elucidating the role of lipids in positive-sense RNA virus infection.

• Applicant: Professorin Dr. Eva Herker
• Subject Area: Virology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416701689

Viruses critically depend on host cell lipid metabolic pathways for infection and replication. All (+) ssRNA viruses usurp host lipids for formation of replication complexes that are surrounded by membranes and contain viral RNA, viral replicase proteins, and host factors. Enveloped viruses additionally need host cell membrane lipids for their shell, and essentially all intracellular pathogens need energy to multiply. We hypothesized that different orthoflaviviruses require common lipid metabolic pathways for successful replication. During the first funding period, we performed lipidomic studies of cells infected with five different orthoflaviviruses to compare and contrast the metabolic rewiring induced by these pathogens. These studies revealed several interesting features of infected cells that we plan to dissect in greater detail in the second funding period. In the first funding period, we identified complex glycerophospholipid remodeling in orthoflavivirus-infected cells. Follow-up mechanistic studies revealed a strong dependency of West Nile and tick-borne encephalitis virus infection on phosphatidylserine synthesis and turnover as well as phosphatidylinositol synthesis. We now propose to dissect these pathways in detail to I) clarify which step of virus replication depends on phosphatidylserine synthesis and turnover and phosphatidylinositol synthesis and if specific inhibitors would function as effective antivirals, II) elucidate the mechanisms of glycerophospholipid conversion, i.e., the activity and localization of the respective enzymes with a specific focus on phosphatidylserine synthesis, turnover, and localization, and III) analyze phosphatidylinositol and phosphoinositide levels, localization, and interconversion in flavivirus infected cells. Taken together our proposed research will significantly contribute to our understanding of how flaviviruses shape their environment for successful multiplication and may identify host targets that may be amendable for future development of antiviral therapies.

• DFG Programme: Research Grants