Joanna L. Shisler
Associate Professor of Microbiology
Host-Pathogen Interactions, Molecular Immunology, Receptor Biochemistry, Signal Transduction, Virology
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
Immune evasion strategies of viruses; viral mechanisms to inhibit intrinsic immune responses; host-pathogen interactions
Viruses are sophisticated pathogens, expressing immune evasion proteins during an infection. This ability to inhibit the immune response is critical for viral replication and induction of pathogenesis. Thus, studying viral immune evasion proteins sheds light on how viruses cause disease. Additionally, these immunoevasion proteins can be the basis for developing new therapeutics or vaccines. Finally, viral immune evasion proteins are excellent tools for deciphering host cell processes of immune responses.
We utilize poxviruses as our model system to identify novel strategies that viruses use to evade the immune response. Poxviruses are large, double stranded DNA viruses. They are important to the medical community because of disease they cause in humans, including smallpox, monkeypox and molluscum contagiosum (see below).
Vaccinia virus and the regulation of NF-κB: The vaccinia poxvirus (Fig. 1) is more than 97% genetically identical to variola and monkeypox viruses, the causative agents of smallpox and monkeypox, respectively. Because of this similarity, vaccinia virus is an excellent model system for understanding how the variola and monkeypox viruses evade the immune system to cause disease. After the eradication of smallpox, vaccinia virus has been used as a vector for vaccines against diseases such as AIDS, malaria and cancer. Thus, our research also aids in the development of safer and more effective vaccine vectors.
The conserved eukaryotic transcription factor nuclear factor-κB (NF-κB) stimulates the expression of proteins that are critical for immune functions. If activated during a virus infection, the NF-κB response can limit viral pathogenesis and resolve the infection. Consequently, many successful viruses employ strategies to inhibit this response. Our investigation of NF-κB activity during poxvirus infection has revealed a novel layer of complexity for this virus/host cell interaction. In our published studies, we demonstrated that the NF-κB response is inhibited when cells are infected with wild-type vaccinia virus, but that it is strongly activated through at least two routes by a highly attenuated vaccinia virus. We recently identified the vaccinia K1L and M2L gene products as NF-κB inhibitory proteins. 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. It is equally interesting to determine how attenuated poxviruses activate NF-κB. We have found that NF-κB activation depends upon early protein synthesis, and we are currently identifying the proteins responsible for this phenotype.
Molluscum contagiosum virus and inhibition TNF: A second poxvirus our lab studies is molluscum contagiosum virus (MCV; Fig. 2). MCV causes a skin infection called molluscum contagiosum (MC). MCV infections are common in children, sexually active adults and immunocompromised patients. MCV causes 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. MCV expresses two proteins, MC159 and MC160, which neutralize the effects of tumor necrosis factor (TNF), an anti-viral cytokine that kills virus-infected cells. By understanding how the MC159 and MC160 proteins inhibit TNF, we will gain insight into how MCV causes persistent infections of the skin. Such knowledge will facilitate the subsequent design of intervention or prevention therapeutics.
Crystall MH Randall and Joanna L Shisler, "Molluscum contagiosum virus:persistence pays off," Future Virology. 8: 561-573, 2013.
Johanna S Salzer, Darren S Carrol, Innocent B Rwego, Yu Li, Elizatbh A Falendysz, Joanna L Shisler, Kevin L Karem, Inger K Damon, Thomas R Gillespie, “Serological Evidence for circulating Orthopoxviruses in peridomestic rodents in rural Uganda,” Journal of Wildlife Diseases, 49:125-131, 2013.
Crystall MH Randall, Janet A Jokela and Joanna L Shisler, "The MC159 protein from the molluscum contagiosum poxvirus inhibits NF-kB activation by interacting with the IKK complex," Journal of Immunology. 188: 2371-2379, 2012.
Stefani M. Martin, Daniel T. Harris and Joanna L. Shisler, “The C11R gene, which encodes the vaccinia growth factor (VGF), is partially responsible for MVA-induced NF-kB and ERK2 activation,” Journal of Virology, 86:9629-9639, 2012.
Kristen L. Willis, Jeffrey O. Langland and Joanna L. Shisler, “Viral dsRNA from vaccinia virus early or intermediate gene transcripts possess PKR activating function, resulting in NF-kappaB activation, when the K1 protein is absent or mutated” Journal of Biological Chemistry. 2011 286:7765-7778.
Willis KL, Patel S, Xiang Y, Shisler JL. The effect of the vaccinia K1 protein on the PKR-eIF2a pathway in RK13 and HeLa cells. Virology 2009; 394:73-81. [Abstract]
Martin S and JL Shisler. Identification of the viral mechanism responsible for NF-kB activation in modified vaccinia Ankara (MVA)-infected fibroblasts. Virology 2009; 390:298-306. [Abstract]
Page MA, Shisler JL, Marinas BJ. Kinetics of adenovirus type 2 inactivation with free chlorine. Water Research 2009; 43: 2916-2926. [Abstract]
Nichols DB and JL Shisler. The poxvirus MC160 protein utilizes multiple mechanisms to inhibit NF-kB activation mediated via components of the tumor necrosis factor receptor-1 signal transduction pathway. Journal of Virology 2009; 83:3162-3174. [Abstract]
Sirikanchana K, Shisler JL, Marinas BJ. Effect of UV-C and monochloramine on early protein expression and DNA replication of adenovirus serotype 2. Applied and Environmental Microbiology 2008; 74:3774-82. Hinthong, O., Jin, X-L. and Shisler, J.L. 2008. Characterization of wild-type and mutant vaccinia virus M2L proteins abilites to localize to the endoplasmic reticulum and to inhibit NF-kappa B activation during infection. Virology, 373: 248-262, 2008. [Abstract]
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, 80 (17): 8676-85. [Abstract]
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., and Moss, B. 1998. UV-induced cell death blocked by a Selenoprotein from a Human Dermatotropic Poxvirus. Science, 279(5347):102-5. [Abstract]