MOLECULAR MIMICRY OF THE INFLAMMATION MODULATORY PROTEINS (IMPS) OF POXVIRUSES - EVASION OF THE INFLAMMATORY RESPONSE TO PRESERVE VIRAL HABITAT

Microorganisms encode numerous immunomodulators that resemble, in stru cture and function, molecules captured over the millennia from their h osts [G. J. Kotwal J. Leukoc. Biol. 62, 415-429]. The vaccinia virus c omplement control protein (VCP) was the first soluble microbial protei n to have a postulated role in the immunomodulation and evasion of hos t defense [G, J. Kotwal and B. Moss Nature 355, 176-179]. Purified bio active VCP has been Shown to bind to C3 and C4, block the complement c ascade at multiple sites [G. J. Kotwal et al, Science 250, 827-830; R. Mckenzie, G. J. Kotwal et al. J. Infect. Dis. 166, 1245-1250] and exh ibit a greater potency than the human complement 4b binding protein, C 4b-BP [G. J. Kotwal, Am. Biotech. Lab. 9,76]. The importance of this p rotein to poxviruses was further demonstrated in rabbits and guinea pi gs through the use of recombinant virus lacking an intact DNA coding f or VCP [Isaacs, G. J. Kotwal, and B. Moss Proc. Natl. Acad. Sci, 89, 6 28-672]. Studies in mice have shown that the homolog of VCP in cowpox virus (CPV), referred to as the inflammation modulatory protein (IMP) can, in a mouse model, significantly diminish the specific footpad swe lling response [C. G. Miller, S. N. Shchelkunov, and G. J. Kotwal Viro l. 229, 126-133], To determine the precise cellular changes at the sit e of infection, BALB/c mice were subcutaneously injected (in the backs ) with CPV or a recombinant virus lacking IMP, CPV-IMP. Differences in histology were observed by staining the adjoining skin tissue section s with hematoxylin & eosin or by removal of the connective tissue and staining with May-Grunwald-Geimsa. All mice that were injected with th e CPV-IMP experienced severe tissue destruction and formation of nodul ar lesions compared with the mice injected with CPV. Microscopic exami nation indicated significantly greater cellular infiltration and destr uction of skeletal muscle cells in the sections of connective tissue a nd adjoining skin tissue, respectively, of the mice injected with the CPV-IMP [G. J. Kotwal et al, Mel. Cell. Biochem. in press]. Thus IMP p reserves the tissue at the site of infection (viral habitat). In this review, we present evidence for molecular mimicry and evolutionary rel ationship to other homologs of IMP and discuss their relationships wit h other IMPs such as the poxviral chemokine and cytokine receptor-like proteins.