The inflammation modulatory protein (IMP) of cowpox virus drastically diminishes the tissue damage by down-regulating cellular infiltration resulting from complement activation.

Abstract

Vaccinia virus (VV) and other pathogenic poxviruses encode for a complement control protein. The VV complement control protein or VCP, was one of the first soluble microbial proteins postulated to have an active role in the immunomodulation of the host defense. Since then, 2 other poxviruses, including variola virus and cowpox virus (CPV), were found to have corresponding proteins. Based upon earlier studies which demonstrated the role of the CPV complement control protein in modulating the specific tissue responses in BALB/c and congenic-matched C5-sufficient and C5-deficient mice, the CPV equivalent has been renamed the inflammation modulatory protein (IMP), so as to specifically reflect its function. In this study, the in vivo cellular response of mice injected with CPV or a recombinant virus lacking the IMP sequence (CPV-IMP) was examined using a connective tissue air pouch model. Microscopic examination revealed that CPV-IMP caused a significant mononuclear cell infiltration into the connective tissue and adjacent dermal tissue of the skin. To characterize IMP's ability to regulate the observed cellular infiltration through both complement derived and non-complement derived chemotactic factors, footpad and skin connective tissue of C3 knockout mice and footpad of MIP-1alpha knockout mice received injections of CPV and CPV-IMP. In comparison to the matched control, significantly greater footpad specific swelling response was seen in C3 -/- mice injected with CPV. This indicates an important role for C3 in poxvirus pathogenesis. However, MIP-1 alpha -/- mice injected with CPV-IMP recovered earlier than mice injected with CPV alone. This indicates that the function of IMP in vivo in mice with a complete repertoire of immune components is to limit cellular infiltration by down regulating the complement derived chemotactic analphylotoxins, thereby modulating the inflammatory response contributing to a diminished tissue pathology and preservation of viral habitat.