Poxviruses encode in their large double-stranded DNA genomes many factors that modify the immune system ( 30, 56). In summary, ectromelia virus produced EMICE within a few hours of an infection, and EMICE in turn decreased complement activation on IMV and infected cells. These results suggest that EMICE's role is early during infection when it counteracts the innate immune response. In contrast, classical pathway activation by high-titer antibody overwhelmed EMICE's regulatory capacity. EMICE on the surface of infected murine cells also reduced complement activation by the alternative pathway. The levels were sufficient in the supernatant to protect the IMV, upon release, from complement-mediated neutralization. Infected murine cells initiated synthesis of EMICE within 4 to 6 h postinoculation.
It accomplished this by serving as a cofactor for the inactivation of C3b and C4b and by dissociating the catalytic domain of the classical pathway C3 convertase. Recombinant EMICE regulated complement activation on the surface of CHO cells, and it protected complement-sensitive intracellular mature virions (IMV) from neutralization in vitro. In this study, we characterized the ectromelia virus inhibitor of complement enzymes (EMICE). Complement's role in the innate and adaptive immune responses likely drove the evolution of a virus-encoded virulence factor that regulates complement activation. We previously demonstrated that multiple components (C3, C4, and factor B) of the classical and alternative pathways are required to survive ectromelia virus infection. Similar to the human pathogen variola virus, ectromelia virus has a limited host range and provides a mouse model where the virus and the host's immune response have coevolved. Poxviruses produce complement regulatory proteins to subvert the host's immune response.