title: A soluble chemokine-binding protein from vaccinia virus reduces virus virulence and the inflammatory response to infection.
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 (v Delta B8R-35K) and characterized its binding properties in vitro and its effect on virulence in vivo relative to wild-type virus (v Delta B8R) or a revertant virus (v Delta B8R-R) where Lister 35-kDa had been removed. Cells infected with v Delta B8R-35K secreted a 35-kDa protein that bound the CC chemokine macrophage-inflammatory protein 1 alpha. 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 1 alpha, eotaxin, and macrophage chemotactic protein 1 were detected in bronchoalveolar lavage fluids from v Delta B8R-infected mice; however, bronchoalveolar lavage fluids from v Delta B8R-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.
authors.affiliation: Department of Virology, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reading
authors.forename: Julian A
authors.initials: JA
authors.lastname: Symons
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D000998:Antiviral Agents / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D002522:Chlorocebus aethiops; D005260:Female; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008171:Lung Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D011995:Recombination, Genetic; D012995:Solubility; D014615:Vaccinia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology*; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014774:Virulence; D037521:Virulence Factors; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; C414049:CCI protein, Cowpox virus; D018925:Chemokines; D019742:Chemokines, CC; D014764:Viral Proteins; D037521:Virulence Factors