Ronald Wek
Indiana University School of Medicine
Toxoplasma and the Stress Response
Addressing the mechanisms of translation control in toxoplasmosis
Toxoplasma gondii is a protozoan parasite that causes life-threatening opportunistic infection in immunocompromised patients, including AIDS patients. The ability of Toxoplasma to convert from its proliferative stage (tachyzoite) to latent tissue cysts (bradyzoite) gives rise to the life-threatening chronic opportunistic disease. There is an urgent need for new therapies to treat toxoplasmosis, but this effort has been stymied by a gap in our knowledge of how the latent stage develops. The mechanisms orchestrating conversion to bradyzoites are poorly understood, but we found that phosphorylation of the Toxoplasma eIF2 coincides with bradyzoite development. We identified Toxoplasma eIF2 kinases and are determining their roles in parasite translational control, survival and differentiation. Furthermore, we are addressing the utility of drugs that modify Toxoplasma eIF2 phosphorylation to illuminate the mechanics of Toxoplasma stage conversion and develop novel therapeutics for toxoplasmosis. These studies are being carried out with our long-standing collaborator Dr. William Sullivan (IUSM), an expert in molecular parasitology.
Toxoplasma tachyzoites proliferative
(cell nuclei stained with DAPI)
Toxoplasma gondii bradyzoite
cyst
(cell nuclei stained with DAPI)
References:
Benmerzouga, I., Checklye, L.A., Ferdig, M.T., Arriazbalaga, G., Wek, R.C., and Sullivan, W.J. (2015) Guanabenz repurposed as an antiparasitic with activity against acute and latent toxoplasmosis. Antimicrobial Agents and Chemotherapy 59, 6939-6945.
Konrad, C., Wek, R.C., Sullivan, W.J. (2014) GCN2-like eIF2α kinase manages the amino acid starvation response in Toxoplasma gondii. International Journal of Parasitology 44,139-146.
Joyce,B.R., Tampaki, Z., Kim, K., Wek, R.C., and Sullivan, W.J. (2013) The unfolded protein response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control. Eukaryotic Cell 12, 979-989.
Konrad, C., Queener, S.F., Wek, R.C., Sullivan, W.J. (2013) Inhibitors of eIF2α dephosphorylation slow replication and stabilize latency in Toxoplasma gondii. Antimicrobial Agents and Chemotherapy 57, 1815-1822.
Konrad, C., Wek, R.C., and Sullivan, W.J. (2011) A GCN2-like eukaryotic initiation factor-2 kinase increases the viability of extracellular Toxoplasma gondii parasites. Eukaryotic Cell 10, 1403-1412.
Joyce, B.R., Queener, S.F., Wek, R.C., and Sullivan, W.J. (2010) Phosphorylation of eukaryotic initiation factor -2a promotes the extracellular survival of obligate intracellular parasite Toxoplasma gondi. Proceedings of National Academy of Science, U.S.A. 107, 17200-17205.
Narasimhan, J., Joyce, B.R., Naguleswaran, A., Smith, A.T., Livingston, M.R., Dixon, S.E., Coppens, I., Wek, R.C. and Sullivan, W.J. (2008) Translation regulation by eIF2 kinases in the development of latent cysts in Toxoplasma gondii. Journal of Biological Chemistry 283 16591-16601.
Sullivan, W.J., Narasimhan, J., Bhatti, B.M., and Wek, R.C. (2004) Parasite-specific eukaryotic initiation factor -2 (eIF2) kinase required for stress-induced translation control. Biochemical Journal, 380, 523-531.