Alec J. Hirsch

Research in Dr. Hirsch’s laboratory is focused on the interactions of the flaviviruses West Nile virus (WNV) and dengue virus (DENV) with the infected cell. Both viruses are mosquito borne pathogens and cause significant morbidity and mortality worldwide. The flaviviruses are single-stranded, positive-sense RNA viruses that replicate in the cytoplasm of the host cell. In order to complete their replication cycles, these viruses interact with multiple cellular proteins and pathways. Using molecular as well as systems biology techniques, Dr. Hirsch’s lab is trying to elucidate pathways within the host cell that are required for virus replication, and how these pathways can be perturbed to inhibit virus replication and identify targets of therapeutic intervention.

A significant area of investigation in the lab is the role played by microRNAs (miRNAs) during flavivirus replication. miRNAs are small (20-22 nt) RNAs that exert translational regulation on target mRNAs through interaction with homologous sequences usually found within the 3’ untranslated region (UTR) of the mRNA. Over 1000 human miRNAs have been identified and likely represent a level of gene regulation every bit as important and complex as that provided by protein transcription factors. Data from our lab and others have demonstrated that viral infection, including infection with DENV and WNV, results in changes in miRNA expression in the host cell. The lab is currently employing several experimental as well as computational methods to determine targets of differentially expressed miRNAs, and asking how miRNA-mediated effects on target expression affect viral replication.

Biography

Alec is an assistant scientist at the Vaccine and Gene Therapy Institute. He received a bachelor’s degree from Swarthmore College (Swarthmore, PA) in 1989. He was awarded a doctoral degree in molecular biology from Princeton University (Princeton, NJ) in 1999, for studies on the effect of human cytomegalovirus on host gene expression. He conducted his postdoctoral work at OHSU.

Key References

Hirsch A.J., Shenk T. (1999) Human cytomegalovirus inhibits transcription of the CC chemokine MCP-1 gene. J. Virol. 73: 404-410. PMCID: PMC103846

Hirsch A.J., Medigeshi G.R., Meyers H.L., DeFilippis V., Fruh K., Briese T., Lipkin W.I., and Nelson J.A. (2005) The Src family kinase c-Yes is required for maturation of West Nile virus particles. J. Virol. 79:11943-11951. PMCID: PMC1212629

Grey F., Hirsch A.J., and Nelson J.A. (2007) Identification and potential function of viral microRNAs. (2007) In: Appansani, K. (ed.) MicroRNAs: From Basic Science to Disease Biology. Cambridge University Press.

Barklis E., Still A., Sabri M.I., Hirsch A.J., Nikolich-Zugich N., Brien J., Dhenub T.C., Scholz I. and Alfadhli A. (2007) Flavivirus inhibition by sultam thioureas. Antimicrob. Agents Chemother. 51: 2642-2645. PMCID: PMC1913232

Medigeshi G.R., Lancaster A.M., Hirsch A.J., Briese T., Lipkin W.I., Mason P.W., Früh K., and Nelson J.A. (2007) West Nile virus infection activates unfolded protein response leading to CHOP induction and apoptosis. J. Virol. 81:10849-10860. PMCID: PMC2045561

Medigeshi G.R., Hirsch A.J., Streblow D.N., Nikolich-Zugich J., and Nelson J.A. (2008) West Nile virus entry requires cholesterol-rich membrane microdomains and is independent of v3 integrin.  J. Virol. 82:5212-5219. PCID: PMC2395215

Medigeshi G.R.*, Hirsch A.J.*, Brien J.D., Uhrlaub J.L., Mason P.W., Wiley C., Nikolich-Zugich,J., and Nelson J.A. (2009) West Nile Virus capsid degradation of claudin proteins disrupts epithelial barrier function. J. Virol, 83:6125-6134. PMCID: PMC2687390
*equal contribution

Brie, J.D., Uhrlaub J.L., Hirsch A.J., Wiley C.A., and Nikolich-Zugich, J. (2009) Key role of T cell defects in age-related vulnerability to West Nile virus. J. Exp. Med. 206:2735-2745. PMCID: PMC2806630

Hirsch A.J. (2010) The use of RNAi-based screens to identify host proteins involved in viral replication. Future Microbiology 5:303. PMCID: PMC2864646

Shum D, Smith J.L., Hirsch A.J., Bhinder B., Radu C., Stein D.A., Nelson J.A., Früh K., and Djaballah H. (2010) High-content assay to identify inhibitors of dengue virus infection. Assay Drug Dev. Technol. Oct;8(5):553-570. PMCID: PMC2962577

Stein D.A., Perry S.T., Buck M.D., Oehmen C.S., Fischer M.A., Poore E., Smith J.L., Lancaster A.M., Hirsch A.J., Slifka M.K., Nelson J.A., Shresta S., and Früh  K. (2011) Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence. J. Virol. 85:10154-10166.