Investigators and Program Directors

Research Interests

Smallpox is a highly communicable disease that has altered human history. The smallpox etiologic agent, variola virus, is a member of the poxvirus family of viruses. Smallpox was successfully eradicated through a concerted worldwide vaccination campaign using the less virulent vaccinia virus. Re-emergence of smallpox is possible through zoonotic transfer from closely related animal poxviruses, or through its potential use as a bioterrorism agent. Given the cessation of the vaccination program, and the potential for the release of modified vaccination-resistant variola virus, it is important to more fully understand its virulence mechanisms to help identify effective antiviral treatments.

My lab is focused on characterizing one poxviral virulence factor variously known as D4R (variola virus), N1R (Shope fibroma virus), or p28 (ectromelia virus). Our model system for studying this gene is ectromelia virus (mousepox). The p28 proteins possess a prominent RING zinc-finger in their C-termini. This motif functions as an E3 ubiquitin ligase that likely identifies specific proteins for ubiquitination and degradation during poxviral infection. We are identifying the targets of p28 using molecular, immunologic, and proteomic techniques. The N-terminal half of p28 may bind to DNA, and we are also investigating this activity as well.

The RING zinc-finger of the p28 proteins closely resembles that of the cellular Makorin protein family. A cellular Mkrn gene appears to have been captured by a poxvirus progenitor, where it was fused to the putative DNA-binding N-terminus, and subsequently trimmed down so that only the RING motif remains in mammalian poxviruses. Captured gene products often interact in the same pathway as their cellular counterparts, in which the poxvirus can then usurp control by activating or antagonizing that pathway. We hypothesize that the poxviral and cellular Makorins have common functions and we are therefore characterizing them in parallel. To this end, we are generating transgenic and knockout mouse models of Makorin family members. We use many molecular (DNA, RNA, protein-based) tools in our analyses of this gene family and the constituent motifs comprising this unique protein.

Contact Information

E-mail:gray@wadsworth.org