Ectromelia virus inhibitor of complement enzymes protects intracellular mature virus and infected cells from mouse complement.
Poxviruses produce complement regulatory proteins to subvert the host's immune response. 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. We previously demonstrated that multiple components (C3, C4, and factor B) of the classical and alternative pathways are required to survive ectromelia virus infection. Complement's role in the innate and adaptive immune responses likely drove the evolution of a virus-encoded virulence factor that regulates complement activation. In this study, we characterized the ectromelia virus inhibitor of complement enzymes (EMICE). Recombinant EMICE regulated complement activation on the surface of CHO cells, and it protected complement-sensitive intracellular mature virions (IMV) from neutralization in vitro. 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. Infected murine cells initiated synthesis of EMICE within 4 to 6 h postinoculation. The levels were sufficient in the supernatant to protect the IMV, upon release, from complement-mediated neutralization. EMICE on the surface of infected murine cells also reduced complement activation by the alternative pathway. In contrast, classical pathway activation by high-titer antibody overwhelmed EMICE's regulatory capacity. These results suggest that EMICE's role is early during infection when it counteracts the innate immune response. 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.
Moulton
Elizabeth A
EA
Department of Medicine/Division of Rheumatology, Washington University School of Medicine, Campus Box 8045, 660 South Euclid Avenue, Saint Louis, Missouri 63110, USA.
Bertram
Paula
P
Chen
Nanhai
N
Buller
R Mark L
RM
Atkinson
John P
JP
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D051056:Complement Inactivating Agents / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology*; D006224:Cricetinae; D003412:Cricetulus; D004481:Ectromelia virus / Q000276:immunology* / Q000472:pathogenicity; D057131:Immune Evasion; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D014764:Viral Proteins / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology*
D051056:Complement Inactivating Agents; D014764:Viral Proteins; D037521:Virulence Factors; D003165:Complement System Proteins