The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

My lab is interested in finding mechanisms that viruses use to evade anti-viral immune responses. Many of these viral “immunoevasion” proteins are also virulence factors. Thus, identifying these viral proteins sheds light on how viruses cause disease. Additionally, these immunoevasion proteins can be developed into therapeutics for pathogen-based or autoimmune diseases. Our lab also utilizes viral proteins as tools to dissect basic cellular processes.

My lab utilizes poxviruses as our model system. Poxviruses are large, double stranded DNA viruses that are important to the medical community because of disease they cause in humans (see below). Since the genomes of over 50 poxviruses have been completely sequenced, much of our hypothesis-driven research is based on identifying ORFs whose products have potential cellular homologs, and then testing whether viral proteins act similar to or as antagonists of their cellular homologs. Also, recombinant and mutant poxviruses are easy to engineer. Thus, it is easy to compare the functions of viruses expressing wild type versus mutant proteins of interest.

One poxvirus our lab studies is vaccinia. Figure 1 shows an electron micrograph of vaccinia viruses, showing the distinct brick-shaped forms of these viruses. Vaccinia virus was the poxvirus used as a vaccine to protect against smallpox. Because vaccinia virus is more than 97% genetically identical to variola virus, the causative agent of smallpox, studies with vaccinia gene products are directly translatable to smallpox. Using this model system, we will have a greater understanding of how vaccinia (and variola) virus evade the immune system to cause disease.

A second poxvirus our lab studies 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).

Using a diverse range of genetic and molecular techniques, I am studying MCV and vaccinia gene products that inhibit the cellular NF-kappa B protein complex. NF-kappa B acts as a transcription factor, controlling the expression of anti-viral and proinflammatory molecules. Thus, poxviruses (and many other viruses) produce proteins to interfere with NF-kappa B, preventing the production of proinflammatory molecules and enhancing virus survival.

We recently identified the vaccinia K1L and M2L gene products as NF-kappa B inhibitory protein (Shisler and Jin and Gedey et al.). We assume that poxviruses express these products to evade immune responses, and survive in the host for longer periods of time. Currently, we are delineating the molecular function of the K1L and M2L viral proteins. 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 (Murao and Shisler) and MC160 (Nichols and Shisler) proteins. We have found that both of these proteins inhibit the NF-kappa B 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.