Interests

Cellular Responses to Viral Infection at the Molecular Level

Titles

Professor of OncologyJoint Appointment in Molecular Biology and Genetics

G. J. Mendel Honorary Medal for Merit in Biological Sciences (2005)

Schools\Degrees

Ph.D., Academy of Sciences, Prague, Czech.

Training

Fellow, Institute of Organic Chemistry and Biochemistry, PragueFellow, Johns Hopkins University School of Medicine

Research Summary

The overall goal of this group is to understand the molecular mechanisms that govern the innate immune response to infectious agents. There is growing evidence which indicates that the inflammatory response plays an important role in autoimmune disease and triggers carcinogenesis. Thus, identification of the critical cellular elements involved in the innate immune recognition of infectious pathogens may provide a lead to our understanding of the role of inflammatory responses in cancer and provide a new therapeutic target.

The long-term goal of Dr. Pitha-Rowe’s research is to understand the cellular responses to infection and the relationship between viral pathogenicity and oncogenicity. Over the past several years, this group has identified three novel transcription factors, IRF-3, IRF-5, and IRF-7, and has shown that these factors serve as direct transporters of virus-mediated signaling. The research advances of this group have revealed a critical role of these factors in expression of the early inflammatory genes in infected cells. This group, together with other laboratories, has shown that these factors are also activated in response to bacterial infection upon binding of ligands to Toll receptors. In their recent studies, this group has shown that over-expression of IRF-5 in B cells induces p21waf and proapoptotic genes in a p53-independent manner.

Altogether, these data indicate that the genes of the IRF family play a critical role in the differentiation and maturation of lymphoid cells, apoptosis and activation of early inflammatory cytokines. Whether IRFs play a role in the innate response to HIV-1 infection also is being examined.The importance of IRFs in innate immunity has been recently demonstrated by the observation that many viruses target their function as a part of viral mimicry. The Kaposi’s sarcoma virus (KSHV) that is associated with Kaposi’s sarcoma and B cell lymphoma encodes four IRF homologues that associate with cellular IRFs and modulate their function, as well as the functions of other cellular proteins.

Clinical Research recent findings of this group have potential clinical application. First, this group has shown that IRFs can serve as an effective adjuvant of DNA-stimulated immune responses to a DNA-encoded viral antigen. These adjuvants will be eventually tested in clinical settings, both for viral infection (HIV-1, HCV) and tumor vaccines. Second, this group has shown that IRF-5 has proapoptotic activity that is independent of p53. Thus, IRF-5 expression may increase sensitivity of p53-defective tumors to proapoptotic drugs. Finally, this group has recently shown that an IFN-induced protein (ISG) is aneffective inhibitor of HIV-1 replication and enhances the virus-mediated antiviral response.

Journal Citations

Pitha, P. M., and M. S. Kunzi. 2007. Type I interferon: The ever unfolding story. Curr Top Microbiol Immunol 316:41-70.

Pitha, P.M. (2008). My interferon years. J Interferon Cytokine Res 28, 699-702.

Pitha-Rowe, I. F., and P. M. Pitha. 2007. Viral defense, carcinogenesis and ISG15: novel roles for an old ISG. Cytokine Growth Factor Rev 18:409-17.

Barnes, B. J., Richards, J., Mancl, M., Hanash, S., Beretta, L., & Pitha, P. M. 2004. Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection. J. Biol. Chem. 279:45194-45207.

Lee, J., Chuang, T. H., Redecke, V., She, L., Pitha, P. M., Carson, D. A., et al. 2003. Molecular basis for the immunostimulatory activity of guanine nuceloside analogs: activation of toll-like receptor 7. Proc. Natl. Acad. Sci. USA. 100:6646-6651. Lubyova, B., Kellum, M. J., Frisancho, A. J., & Pitha, P. M. 2004. Kaposi's sarcoma-associated herpesvirus vIRF-3 stimulates the transcriptional activity of cellular IRF-3 and IRF-7. J. Biol. Chem. 279:7643-7654.

Pitha, P. M. 2004. Cell defence against viral/bacterial infections: closer mechanism than anticipated? Folia Biol.-Prague. 50:93-99.

Pitha, P. M. 2004. Unexpected similarities in cellular responses to bacterial and viral invasion. Proc. Natl. Acad. Sci. USA. 101:695-696.

Redecke, V., Hacker, H., Datta, S. K., Fermin, A., Pitha, P. M., Broide, D. H., et al. 2004. Cutting edge: activation of toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J. Immunol. 172:2739-2743.