Infection-specific lipid metabolism as a target to control enterovirus infections

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Project Summary Infection-specific lipid metabolism as a target to control enterovirus infections The development of the membranous replication organelles is a crucial step in the life cycle of all positive-strand RNA viruses of eukaryotes, including enteroviruses. The unique lipid and protein composition of the replication organelles is essential for the functioning of the viral enzymatic replication machinery, and the membranes likely hide the replication complexes containing dsRNA from the sensors and effectors of the cellular anti-viral response. In the case of enteroviruses, the structural and functional development of the replication organelles requires a profound reconfiguration of the cellular lipid synthesis and membrane metabolism pathways. Recently we and others demonstrated that diverse enteroviruses universally engage lipid droplets, dynamic cellular organelles that regulate the lipid metabolism, to support the development of the replication organelles. The emerging picture shows that enterovirus infection results in: 1) activation of lipolysis of neutral lipids stored in lipid droplets, liberating free long-chain fatty acids; 2) activation of long chain-acyl-CoA synthetases whose activity is necessary to re-route the long-chain fatty acids into metabolic processes in the form of acyl-CoAs, and 3) redirection of the newly-synthesized acyl-CoAs into the synthesis of structural phospholipids, providing membranes for the expansion of the replication organelles. We hypothesize that the influx of free long-chain fatty acids triggers the subsequent changes in the lipid metabolism of infected cells. Our data also demonstrate that by targeting different pathways of lipid metabolism it is possible to make the replication more sensitive to the innate immunity mechanisms, or to specifically eliminate the infected cells, providing a new perspective on the control of enterovirus infections. Here, we formed a team of experts in virology and lipid research to use biochemical, cell biology, innovative microscopy and proteomics methods to investigate the changes in lipid metabolism in enterovirus-infected cells. We will focus on the activation of lipid droplet lipolysis and engagement of acyl-CoA synthetases because they define the landscape of lipid metabolism in infected cells. We will also investigate the role of the structural expansion of the replication organelles in the protection of the replication complexes and explore the vulnerabilities of infected cells conferred by the reconfiguration of the lipid synthesis pathways. We will use enteric and respiratory airway epithelia ex-vivo systems to study the role of rewiring lipid metabolism in relevant cells upon infection of diverse enteroviruses. We believe that this project will significantly advance the fundamental knowledge of lipid metabolism in infected cells, broadly relevant for virology and cell biology, and will open new perspectives for the development of interventions effective against diverse enteroviruses.