Research topicsDepartment of Microbiology
Ph.D. (1996) Emory University
Research topics
- Viral regulation of immune responses
- Viral proteins regulating apoptosis
- Poxvirus-host interactions
Research Interests
My laboratory delineates mechanisms viruses use to evade anti-viral immune responses, using poxviruses as a model system.
Poxviruses are large, double stranded DNA viruses that are important to the medical community because of disease they cause in humans. Smallpox, caused by the variola virus, is the most famous disease caused by poxviruses. This virus killed 1 in every 3 people before it was eradicated in the 1970s. While smallpox no longer exists in the wild, the U.S. government is concerned that it can be used as a bioterror agent.
Vaccinia virus was the poxvirus used as a vaccine to protect against smallpox. Vaccinia virus is genetically and antigenically related to variola virus, which is why it was able to protect people from smallpox. Vaccinia virus is also a successful vaccine vector for other diseases, such as AIDS and malaria. Because vaccinia virus is more than 97% genetically identical to the smallpox virus, studies with vaccinia gene products are directly translatable to smallpox. Figure 1 shows an electron micrograph of vaccinia viruses, showing the distinct brick-shaped forms of these viruses.
A benign poxvirus is molluscum contagiosum virus (MCV). MCV causes a very common non-lethal infection, affecting children, sexually active adults and immunocompromised patients. MCV infects only keratinocytes, inducing skin lesions, or “pocks” that are small, but persist for months before spontaneously resolving. These lesions are much larger and persist for longer periods of time in immunocompromised patients. It is of great interest to determine the mechanisms MCV utilizes to persist for such lengthy periods, specifically focusing on the immunomodulatory proteins MCV produces to fight anti-viral immune responses. There are many MCV proteins that have already been shown to inhibit immune responses (Figure 2).
The genomes of over 50 poxviruses have been completely sequenced, allowing us to easily discover viral proteins that are homologous to other know cellular and viral proteins. Also, recombinant and mutant poxviruses are easy to engineer, making functional studies of viral proteins within the context of the virus life cycle possible.
Using a diverse range of genetic and molecular techniques, I am studying MCV and vaccinia gene products that inhibit the cellular NF-kB protein complex. NF-kB acts as a transcription factor, controlling the expression of anti-viral and proinflammatory molecules. Thus, poxviruses (any many other viruses) produce proteins to interfere with NF-kB, preventing the production of proinflammatory molecules and enhancing virus survival.
We recently identified the vaccinia K1L product as an NF-kB inhibitory protein (Shisler and Jin reference below). Viruses lacking the K1L gene induce NF-kB during infection, resulting in the production of proinflammatory molecules. In contrast, NF-kB is inactive in cells infected with viruses that contain the K1L gene. We assume that poxviruses possess K1L to evade immune responses and survive in the host for longer periods of time. In the near future, we will test whether deletion of the K1L gene affects the pathogenicity of a poxvirus infection in an animal model.
Other studies in my laboratory have focused on the function of the MCV MC159 and MC160 proteins. We have found that both of these proteins inhibit the NF-kB transcription factor. Other dermatotropic viruses, like herpesviruses, produce similar immuno-evasion proteins. Thus, work delineating MCV persistence mechanisms will lead to a greater understanding of persistent infections of the skin and facilitate subsequent design for intervention or prevention treatments.
Figure 1.
Figure 2.
Key Words Tissue Culture, Virology, signal Transduction Pathway Analysis,
Introduction of DNA into Animal Cells, Cytokines, Apoptosis