Work published in the Proceedings of the National Academy of Sciences by Rosengard and colleagues helps to explain one way in which variola virus, the causative agent of smallpox, successfully evades the human immune system, resulting in a mortality rate of 30–40% of infected individuals.

Variola virus specifically infects humans, and it is the most virulent member of the Orthopoxvirus family. By contrast, the closely related vaccinia virus causes no disease in humans. The difference in severity between these two Orthopoxvirus infections depends on host innate immune responses — including the complement system, which acts to destroy viruses and virus-infected cells — as well as viral immune-evasion mechanisms.

A better understanding of variola pathogenesis is required to develop a safer vaccine, but World Health Organization directives and ethical concerns preclude in vivo work on variola virus. As authentic variola proteins are unavailable, the authors used molecular-engineering techniques to characterize the complement-regulatory proteins (CRPs) of variola virus and vaccinia virus, and they compared their effectiveness in overcoming human complement activation.

The CRP that is encoded by smallpox —smallpox inhibitor of complement enzyme (SPICE) — was generated by site-directed mutagenesis from its homologue, the vaccinia-virus virulence factor vaccinia-virus complement-control protein (VCP). CRPs function as co-factors for the serine protease factor I to cleave C3b and C4b into inactive fragments. C3b- and C4b-degradation experiments showed that SPICE is ∼100-fold more potent than VCP at inactivating human C3b and sixfold more potent at inactivating C4b. These results indicate that SPICE might be a virulence factor for variola virus by protecting variola-infected cells from complement-mediated attack.

Next, the authors investigated the species preferences of these CRPs. SPICE preferentially inhibited human and baboon complement, whereas VCP preferentially inhibited dog and guinea-pig complement. These results show that variola virus exhibits human preference at a protein level, which potentially explains the preference of variola virus for a human host.

Variola proteins are, therefore, specifically able to evade the human immune response, and if smallpox were to re-emerge, SPICE might be a new therapeutic target.