The possible re-emergence of Variola virus, the causative agent of smallpox, as a potential bioterrorism agent has led to renewed interest in the pathogenesis of smallpox and in the development of therapies and safer vaccines. Variola virus, as the most virulent member of orthopoxviruses, specifically infects humans and has no other animal reservoir. As smallpox was eradicated before techniques for the manipulation of DNA were widely available, very few molecular studies of this virus are available, and the Variola virus itself, its genomic DNA and its proteins are not available to the general scientific community. Another orthopoxvirus, Vaccinia, shares remarkable DNA homology, and was used in the global eradication of smallpox, which ended in the late 1970s.
Among many proteins encoded by Variola virus, over 80 are located in the terminal regions of the genome, where proteins associated with host immune evasion1 are encoded. To date, only two Variola proteins have been characterized: smallpox inhibitor of complement enzymes (SPICE) and a high-affinity secreted chemokine-binding protein type II.
A recent paper published in the Proceedings of the National Academy of Sciences has demonstrated a molecular approach to engineer SPICE, a homologue of a Vaccinia virulence factor, Vaccinia virus complement control protein (VCP). SPICE coding sequence was generated from that of VCP by site-directed mutagenesis, and recombinant SPICE and VCO were produced in mammalian and insect cells and affinity purified. SPICE and VCP demonstrate a preference for complement from different species in hemolytic experiments. SPICE efficiently prevents the stabilitization of human C3b and C4b, inactivates the convertases, and consequently decreases the production of inflammatory mediators C3a, C4a, and C5a. Furthermore, SPICE is nearly 100-fold more potent than VCP at inactivating human C3b and six-fold more potent at inactivating C4b, and is also more human-specific than VCP.
‘Assuming that complement is as critical to orthopoxvirus containment in humans as it is in rodents, SPICE seems to be a virulence factor for Variola virus’, said Ariella Rosengard,2 the principal investigator of the research. Disabling SPICE could represent an approach for the treatment of smallpox, and disabling VCP could represent an approach for the development of a safer smallpox vaccine.
These studies help to understand the pathogenesis of smallpox and may also assist in the development of targeted therapies for the treatment of smallpox.
Dunlop LR, Oehlberg KA, Reid JJ, et al. Variola virus immune evasion proteins. Microbes Infect 2003;5(11):1049–1056.
Rosengard AM, Liu Y, Nie Z, et al. Variola virus immune evasion design: expression of a highly efficient inhibitor of human complement. Proc Natl Acad Sci USA 2002;99(13:8808–8813.
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SPICE: Variola virus virulence factor and potential target for therapy. Lab Invest 84, 6 (2004). https://doi.org/10.1038/labinvest.3700017