Poxviruses package viral redox proteins in lateral bodies and modulate the host oxidative response

All poxviruses contain a set of proteinaceous structures termed lateral bodies (LB) that deliver viral effector proteins into the host cytosol during virus entry. To date, the spatial proteotype of LBs remains unknown. Using the prototypic poxvirus, vaccinia virus (VACV), we employed a quantitative comparative mass spectrometry strategy to determine the poxvirus LB proteome. We identified a large population of cellular proteins, the majority being mitochondrial, and 15 viral LB proteins. Strikingly, one-third of these comprise the full set of VACV redox proteins whose LB residency could be confirmed using super-resolution microscopy. We further show that VACV infection exerts an anti-oxidative effect on host cells and that artificial induction of oxidative stress impacts early gene expression and virion production. In addition to defining the spatial proteotype of these enigmatic viral structures, these findings implicate poxvirus redox proteins as modulators of host oxidative anti-viral responses and provide a solid starting point for future investigations into the role of LB resident proteins in host immunomodulation.