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

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.

Grant Number: 5R01AI169458-05
NIH Institute/Center: NIH
Principal Investigator: George Belov