Joanna L. Shisler
Assistant Professor of
Microbiology
jshisler@life.uiuc.edu
B.A. (Microbiology), Miami University,
1990
Ph.D. (Immunology and Molecular Pathogenesis), Emory University,
1996
Postdoctoral (Virology), Laboratory of Viral Diseases,
National Institutes of Health, 1997-2001
Strategies human poxviruses utilize to evade the immune response; viral mechanisms to dampen inflammation
My lab is interested in finding mechanisms that viruses use to evade anti-viral immune responses.
We use 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 testing whether viral proteins act similar to 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 well-known poxviruses includes variola virus, the causative agent of smallpox. . This disease 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.
One poxvirus our lab studies is vaccinia. Vaccinia virus was the poxvirus used as a vaccine to protect against smallpox. Because vaccinia virus is more than 97% genetically identical to the smallpox virus, studies with vaccinia gene products are directly translatable to smallpox. Using this model system, we will have a greater undestanding of how vaccinia and variola evade the immune system to cause disease. Figure 1 shows an electron micrograph of vaccinia viruses, showing the distinct brick-shaped forms of these viruses.
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-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 and M2L products as NF-kB inhibitory protein (Shisler and Jin, and Gedey et al.)). 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 (Murao and Shisler) and MC160 (Nichols and Shisler) 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.
Gedey, R., Jin, X.-L., Hinthong, O. and Shisler, J.L. (2006) Poxviral regulation of the host NF-kappa B response: The vaccinia M2L protein inhibits the induction of NF-kappa B activation via an ERK2 pathway in virus-infected human embryonic kidney cells. Journal of Virology, in press.
Nichols, D.B. and Shisler, J.L. (2006) The MC160 protein from a dermatotropic poxvirus prevents TNF-alpha-induced NF-kB activation and inactivates the IKK complex. Journal of Virology 80(2):578-86. [Abstract]
Murao, L. and Shisler, J.L. (2005) The MCV MC159 protein inhibits late, but not early, events of TNF-alpha-mediated-induced NF-kB activation. Virology 340(2):255-64. [Abstract]
Shisler, J.L. and Jin, X.-L. (2004) The vaccinia virus K1L gene product inhibits host NF-kappa B activation by preventing I kappa B alpha degradation. Journal of Virology 78(7): 3553-60. [Abstract]
Chan, F., Shisler, J.L.,Bixby, J.G., Felices, M., Zheng, L., Appel, M., Orenstein, J., Moss, B., and Lenardo, M.J. (2003) A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. Journal of Biological Chemistry 278(51): 51613-21. [Abstract]
Shisler, J.L. and Moss, B. (2001) The MCV MC159 product blocks Fas-induced apoptosis during a poxvirus infection by prevention of pro-caspase and MC160 activation. Virology 282:14-25. [Abstract]
Moss, B., Shisler, J.L., Xang, Y., and Senkevich, T. (2000) Immune-defense Molecules of Molluscum Contagiosum Virus: a Human Poxvirus. Trends in Microbiology 8(10):473-7. [Abstract]
Shisler, J.L., Isaacs, S., and Moss, B. (1999) Vaccinia virus serpin-1 deletion mutant exhibits a host range defect characterized by low levels of intermediate and late mRNAs. Virology 262(2): 298-311. [Abstract]
Shisler, J.L., Senkevich, T., Berry, M.J., Moss, B. (1998) UV-induced Cell Death Blocked by a Selenoprotein from a Human Dermatotropic Poxvirus. Science 279(5347):102-5. [Abstract]
View Joanna L. Shisler's publications at the National Library of Medicine (PubMed)