Variola virus, the most virulent member of the genus Orthopoxvirus, specifically infects humans and has no other animal reservoir.
Variola causes the contagious disease
smallpox, which has a 30-40% mortality rate. Conversely, the prototype orthopoxvirus,
vaccinia, causes no disease in immunocompetent humans and was used in the global eradication of
smallpox, which ended in 1977. However, the threat of
smallpox persists because clandestine stockpiles of
variola still exist. Although
variola and
vaccinia share remarkable
DNA homology, the strict human tropism of
variola suggests that its
proteins are better suited than those of
vaccinia to overcome the human immune response. Here, we demonstrate the functional advantage of a
variola complement regulatory
protein over that of its
vaccinia homologue. Because authentic
variola proteins are not available for study, we molecularly engineered and characterized the
smallpox inhibitor of
complement enzymes (SPICE), a homologue of a
vaccinia virulence factor,
vaccinia virus complement control protein (VCP). SPICE is nearly 100-fold more potent than VCP at inactivating human C3b and 6-fold more potent at inactivating C4b. SPICE is also more human
complement-specific than is VCP. By inactivating
complement components, SPICE serves to inhibit the formation of the C3/C5 convertases necessary for
complement-mediated viral clearance. SPICE provides the first evidence that
variola proteins are particularly adept at overcoming human immunity, and the decreased function of VCP suggests one reason why the vaccinia virus
vaccine was associated with relatively low mortality. Disabling SPICE may be therapeutically useful if
smallpox reemerges.