Viral growth factor- and STAT3 signaling-dependent elevation of the TCA cycle intermediate levels during vaccinia virus infection

Metabolism is a crucial frontier of host-virus interaction as viruses rely on their host cells to provide nutrients and energy for propagation. Vaccinia virus (VACV) is the prototype poxvirus. It makes intensive demands for energy and macromolecules in order to build hundreds and thousands of viral particles in a single cell within hours of infection. Our comprehensive metabolic profiling reveals profound reprogramming of cellular metabolism by VACV infection, including increased levels of the intermediates of the tri-carboxylic acid (TCA) cycle independent of glutaminolysis. By investigating the level of citrate, the first metabolite of the TCA cycle, we demonstrate that the elevation of citrate depends on VACV-encoded viral growth factor (VGF), a viral homolog of cellular epidermal growth factor. Further, the upregulation of citrate is dependent on STAT3 signaling, which is activated non-canonically at the serine727 upon VACV infection. The STAT3 activation is dependent on VGF, and VGF-dependent EGFR and MAPK signaling. Together, our study reveals a novel mechanism by which VACV manipulates cellular metabolism through a specific viral factor and by selectively activating a series of cellular signaling pathways.