Abstract
Vaccinia virus (VACV) is a large DNA virus that replicates in the cytoplasm and encodes about 200 proteins of which approximately 50 % may be non-essential for viral replication. These proteins enable VACV to suppress transcription and translation of cellular genes, to inhibit the innate immune response, to exploit microtubule- and actin-based transport for virus entry and spread, and to subvert cellular metabolism for the benefit of the virus. VACV strain WR protein C16 induces stabilization of the hypoxia-inducible transcription factor (HIF)-1α by binding to the cellular oxygen sensor prolylhydroxylase domain-containing protein (PHD)2. Stabilization of HIF-1α is induced by several virus groups, but the purpose and consequences are unclear. Here, 1H-NMR spectroscopy and liquid chromatography-mass spectrometry are used to investigate the metabolic alterations during VACV infection in HeLa and 2FTGH cells. The role of C16 in such alterations was examined by comparing infection to WT VACV (strain WR) and a derivative virus lacking gene C16L (vΔC16). Compared with uninfected cells, VACV infection caused increased nucleotide and glutamine metabolism. In addition, there were increased concentrations of glutamine derivatives in cells infected with WT VACV compared with vΔC16. This indicates that C16 contributes to enhanced glutamine metabolism and this may help preserve tricarboxylic acid cycle activity. These data show that VACV infection reprogrammes cellular energy metabolism towards increased synthesis of the metabolic precursors utilized during viral replication, and that C16 contributes to this anabolic reprogramming of the cell, probably via the stabilization of HIF-1α.
Highlights
Vaccinia virus (VACV) is the prototypic member of the genus Orthopoxvirus of the family Poxviridae
VACV is still studied intensively due to its role in vaccine development and because VACV is an excellent model for studying virus–host interactions, such as immune evasion (Smith et al, 2013)
VACV infection has a dramatic impact on cells, but the metabolic alterations that accompany the early stages of VACV infection have only recently started to be investigated
Summary
Vaccinia virus (VACV) is the prototypic member of the genus Orthopoxvirus of the family Poxviridae. Resting cells (Buller et al, 1988a, b) and several enzymes involved in nucleotide metabolism, such as ribonucleotide reductase (Slabaugh et al, 1988; Tengelsen et al, 1988), thymidine kinase (Hruby & Ball, 1982; Weir et al, 1982), thymidylate kinase (Hughes et al, 1991; Smith et al, 1989b), dUTPase (Broyles, 1993; McGeoch, 1990) and uracil DNA glycosylase (De Silva & Moss, 2003, 2008). Two studies reported increased glutamine utilization (Fontaine et al, 2014) and de novo fatty acid biosynthesis (Greseth & Traktman, 2014) during VACV infection
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