Central carbon metabolism is an intrinsic factor for optimal replication of a norovirus

The metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can therefore be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics profile of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus infection. Inhibiting glycolysis with 2-deoxyglucose (2DG) in transformed and primary macrophages revealed that host cell metabolism is an important factor for optimal murine norovirus (MNV) infection. 2DG affected an early stage in the viral life cycle after viral uptake and capsid uncoating, leading to decreased levels of viral protein translation and viral RNA replication. The requirement of central carbon metabolism was specific for MNV (but not astrovirus) infection, independent of the Type I interferon antiviral response, and unlikely to be due to a lack of host cell nucleotide synthesis. MNV infection increased activation of the protein kinase Akt, but not AMPK, two master regulators of cellular metabolism, suggesting Akt signaling may play a role in upregulating central carbon metabolism during norovirus infection. In conclusion, our findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates metabolism as a virulence determinant. They further implicate cellular metabolism as a novel therapeutic target for norovirus infections and improvements of current human norovirus culture systems.