forrest

Associate Professor, Department of Microbiology & Immunology 

Research Interest:  Mechanisms of Gammaherpesvirus Pathogenesis
Ph.D., Vanderbilt University, Nashville, TN
Postdoctoral:  Emory University School of Medicine, Atlanta, GA
Phone: (501) 526-7141
Fax:     (501) 686-535

E-mail

Research Description

Mechanisms of Gammaherpesvirus Pathogenesis

Gammaherpesviruses are DNA tumor viruses that establish lifelong persistent infections in host lymphocytes and other cell types. Here they have the capacity to cause disease through the expression of viral gene products that alter normal cellular signaling pathways that would otherwise facilitate the maintenance of host homeostasis. This is illustrated by the long list of malignancies associated with infection by Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus, human gammaherpesviruses found in Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, gastric carcinoma, primary effusion lymphoma, Kaposi sarcoma and multicentric Castleman disease, among others. Moreover, epidemiology suggests that greater than 90% of adults are chronically infected with EBV. This high prevalence emphasizes the importance of understanding each step in the gammaherpesvirus infectious cycle toward the prevention and treatment of gammaherpesvirus-associated cancers.

Research in the Forrest laboratory utilizes murine gammaherpesvirus-68 (MHV68), a rodent pathogen genetically related to EBV and KSHV, to define virus and host determinants of disease. Our research employs the main strengths of the MHV68 system, robust replication in culture, ready genetic manipulation, and a small animal pathogenesis model to define mechanisms by which conserved gammaherpesvirus gene products manipulate host tumor suppressor pathways. We are currently focused on defining functions of the MHV68 latency-associated nuclear antigen (mLANA) in productive viral replication and long-term viral persistence. LANA expression is a defining characteristic of KSHV-related disease, which is highlighted by several studies demonstrating potential roles for LANA in disrupting host tumor suppressor pathways in tumor cells and overexpression systems. Yet, roles for these LANA functions in productive viral replication and persistence have not been explored. Our work seeks to define LANA interactions with cellular and viral proteins and promoters, as well as the post-translational modifications that regulate these events, in the context of natural infections. These studies will provide a better understanding of basic mechanisms of gammaherpesvirus replication and persistence and enhance an appreciation of factors that contribute to gammaherpesvirus-related diseases.

References

Paden, C.R., Forrest, J.C., Tibbetts, S.A., and Speck, S.H. Unbiased mutagenesis of MHV68 LANA reveals a DNA-binding domain required for LANA function in vitro and in vivo. PLOS Pathog. Sep;8(9):e1002906. 2012. (PMCID: PMC3435236)

Stahl, J.A., Paden, C.R., Chavan, S.S., Macleod, V., Edmondson, R.D., Speck, S.H., and Forrest, J.C. Amplification of JNK signaling is necessary to complete the MHV68 lytic replication cycle. J. Virol. 86(24):13253-62. 2012. (PMCID: PMC3503053)

Stahl, J.A., Chavan, S.S., Sifford, J.M., Macleod, V., Voth, D.E., Edmondson, R.D., and Forrest, J.C. Phosphoproteomic analyses reveal signaling pathways that facilitate lytic gammaherpesvirus replication. PLOS Pathog. Sep;9(9):e1003583. 2013. (PMCID: PMC3777873)

Coleman, C.B, McGraw, J.E., Feldman, E.R., Roth, A.N., Keyes, L.R., Grau, K.R., Cochran, S.L., Waldschmidt, T.J., Liang, C., Forrest J.C., and Tibbetts, S.A. A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo. PLOS Pathog. Feb;10(2):e1003916. 2014. (PMCID: PMC3916410)

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