THE INFLAMMATION MODULATORY PROTEIN (IMP) OF COWPOX VIRUS DRASTICALLYDIMINISHES THE TISSUE-DAMAGE BY DOWN-REGULATING CELLULAR INFILTRATIONRESULTING FROM COMPLEMENT ACTIVATION

Vaccinia virus (VV) and other pathogenic poxviruses encode for a compl ement control protein. The VV complement control protein or VCP, was o ne of the first soluble microbial proteins postulated to have an activ e role in the immunomodulation of the host defense. Since then, 2 othe r poxviruses, including variola virus and cowpox virus (CPV), were fou nd to have corresponding proteins. Based upon earlier studies which de monstrated the role of the CPV complement control protein in modulatin g the specific tissue responses in BALB/c and congenic-matched C5-suff icient and CS-deficient mice [1], the CPV equivalent has been renamed the inflammation modulatory protein (IMP), so as to specifically refle ct 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. Microsco pic examination revealed that CPV-IMP caused a significant mononuclear cell infiltration into the connective tissue and adjacent dermal tiss ue of the skin. To characterize IMP's ability to regulate the observed cellular infiltration through both complement derived and non-complem ent derived chemotactic factors, footpad and skin connective tissue of C3 knockout mice and footpad of MIP-1 alpha knockout mice received in jections of CPV and CPV-IMP. In comparison to the matched control, sig nificantly 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-I alpha -/- mice injected with CPV -IMP recovered earlier than mice injected with CPV alone. This indicat es that the function of IMP in vivo in mice with a complete repertoire of immune components is to limit cellular infiltration by down regula ting the complement derived chemotactic analphylotoxins, thereby modul ating the inflammatory response contributing to a diminished tissue pa thology and preservation of viral habitat.