The role of Smad signalling during vaccinia virus infection

Abstract

Vaccinia virus (VACV) is considered the prototypical poxvirus and is a common therapeutic agent, especially in the fields of vector and oncolytic research. In this last case, understanding viral-host interactions is crucial for developing targeted anti-cancer treatments. One aspect of interest is the VACV infection phenotype, which is typified by alterations to cell structure, adoption of motility and manipulation of host transcription. These features are reminiscent of a host process – epithelial-to-mesenchymal transition (EMT). Given the parallels between EMT and VACV infection, we wanted to ascertain if classical pathways, which modulate mesenchymal transitions, are activated by VACV. Using various techniques, we found that VACV induces TGF-β signalling at both the transcriptional and protein levels, promoting an EMT-like phenotype. Our results suggest that VACV utilises a transcription factor in this pathway, Smad4, for efficient cell-to-cell spread, replication and induction of cell migration. As other microbes induce EMT to promote infection spread and pathogenesis, we theorised this was the case for VACV. However, unlike these other contexts, this process appears entirely independent of the canonical TGF-β receptor during VACV infection. Further investigation showed this feature to be unique to VACV as it did not occur in infection with related poxvirus, Ectromelia virus (ECTV). Phenotypic and transcriptomic characterisation revealed a potential role for vaccinia viral growth factor (VGF) in the activation of TGF-β signalling during infection. Whether this is via direct interaction, or actions of related cross-talk pathway, the epidermal growth factor receptor (EGFR) pathway, is yet to be determined. Given that the TGF-β and EGFR pathways are aberrantly regulated during tumour development, and VACV is a potent oncolytic agent, this research could provide us with information to hone oncolytic agents.