Modulation of nucleotide metabolism by picornaviruses

Viruses actively reprogram the metabolism of the host to ensure the availability of sufficient building blocks for virus replication and spreading. However, relatively little is known about how picornaviruses-a large family of small, non-enveloped positive-strand RNA viruses-modulate cellular metabolism for their own benefit. Here, we studied the modulation of host metabolism by coxsackievirus B3 (CVB3), a member of the enterovirus genus, and encephalomyocarditis virus (EMCV), a member of the cardiovirus genus, using steady-state as well as 13C-glucose tracing metabolomics. We demonstrate that both CVB3 and EMCV increase the levels of pyrimidine and purine metabolites and provide evidence that this increase is mediated through degradation of nucleic acids and nucleotide recycling, rather than upregulation of de novo synthesis. Finally, by integrating our metabolomics data with a previously acquired phosphoproteomics dataset of CVB3-infected cells, we identify alterations in phosphorylation status of key enzymes involved in nucleotide metabolism, providing insight into the regulation of nucleotide metabolism during infection. The family Picornaviridae includes many well-known human and animal pathogens. These include the enteroviruses (e.g. poliovirus, coxsackievirus, EV-A71, EV-D68, and rhinoviruses), which cause a variety of diseases ranging from hand-foot-and-mouth disease, myocarditis, and conjunctivitis to aseptic meningitis and acute flaccid paralysis, as well as animal pathogens such as foot-and-mouth disease virus and encephalomyocarditis virus. Upon infection of their host, these viruses modulate several cellular processes for efficient replication and spreading, such as host cell gene expression, intracellular protein and membrane transport, and cell death pathways. However, little is known about the effects of picornaviruses on cellular metabolism. We here show that picornaviruses modulate nucleotide metabolism by inducing nucleic acid degradation and nucleotide recycling, while restricting nucleotide de novo synthesis. Insight into picornaviral modulation of cellular metabolism is important to increase our understanding of picornavirus-host interactions and may uncover novel therapeutic strategies.