A Soluble Chemokine-Binding Protein from Vaccinia Virus Reduces Virus Virulence and the Inflammatory Response to Infection
Reading PC., Symons JA., Smith GL.
Abstract Many poxviruses express a secreted protein that binds CC chemokines with high affinity and has been called viral CC chemokine inhibitor (vCCI). This protein is unrelated to any known cellular protein, yet can compete with host cellular CC chemokine receptors to modulate host inflammatory and immune responses. Although several strains of vaccinia virus (VV) express a vCCI, the best characterized VV strains Western Reserve and Copenhagen do not. In this study, we have expressed the vCCI from VV strain Lister in a recombinant Western Reserve virus (vΔB8R-35K) and characterized its binding properties in vitro and its effect on virulence in vivo relative to wild-type virus (vΔB8R) or a revertant virus (vΔB8R-R) where Lister 35-kDa had been removed. Cells infected with vΔB8R-35K secreted a 35-kDa protein that bound the CC chemokine macrophage-inflammatory protein 1α. Expression of vCCI attenuated the virus in a murine intranasal model, characterized by reduced mortality and weight loss, decreased virus replication and spread, and a reduced recruitment of inflammatory cells into the lungs of VV-infected mice. The CC chemokines macrophage-inflammatory protein 1α, eotaxin, and macrophage chemotactic protein 1 were detected in bronchoalveolar lavage fluids from vΔB8R-infected mice; however, bronchoalveolar lavage fluids from vΔB8R-35K-infected mice had lower levels of chemokines and a reduced chemotactic activity for murine leukocytes in vitro. These observations suggest that vCCI plays an important role in regulating leukocyte trafficking to the lungs during VV infection by binding to CC chemokines and blocking their chemotactic activities.