Toxoplasmosis and the Stress Response

Addressing the roles of eIF2 phosphorylation and translation control in parasite cyst formation and 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.

Toxoplasmosis

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. Stress is a critical inducer of cyst development and we discovered that phosphorylation of the Toxoplasma eIF2 occurs during with bradyzoite development. Multiple Toxoplasma eIF2 kinases respond to different stresses, convering translational control. We are addressing the roles that translational control plays in cyst development and reemergence of Toxoplasma tachyzoites.

Our studies are are being carried out with our long-standing collaborator Dr. William Sullivan (IUSM), an expert in molecular parasitology, and we aim to develop new strategies for erradication of parasite cysts and treatment of toxoplasmosis.

Toxoplasma tachyzoites proliferative

(cell nuclei stained with DAPI)

Toxoplasma gondii bradyzoite cyst

(cell nuclei stained with DAPI)

References:

Holmes MJ, Bastos MS, Dey V, Severo V, Wek RC, Sullivan WJ Jr. (2023)

mRNA cap-binding protein eIF4E1 is a novel regulator of Toxoplasma gondiilatency bioRxiv [Preprint] Oct 9

Augusto L, Wek RC and Sullivan WJ Jr (2021)

Host sensing and signal transduction during Toxoplasma stage conversion Molecular Microbiology May;115(5): 839-848

Augusto L, Martynowicz J, Amin PH, Carlson KR, Wek RC, Sullivan WJ Jr (2021)

TgIF2-B is an eIF2 kinase in Toxoplasma gondii that responds to oxidative stress and optimizes pathogenicity.

mBio Jan 26;12(1) :c03160-20

Augusto, L, Martynowicz J, Amin PH, Alakhras NS, Kaplan MH, Wek RC, Sullivan WJ Jr (2020)

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells. mBio Jul7;11(4)

Augusto L, Amin PH, Wek RC, Sullivan WJ Jr (2019)

Regulation of arginine transport by GCN2 eIF2 kinase is important for replication of the intracellular parasite Toxoplasma gondii.

PLoS Pathog Jun 13:15(6)

Holmes MJ, Shah P, Wek RC, Sullivan WJ Jr (2019)

Simultaneous Ribosome Profiling of Human Host Cells Infected with Toxoplasma gondii. mSphere Jun 5;4(3)

Augusto L, Martynowicz J, Staschke KA, Wek RC, and Sullivan WJ Jr (2018)

Effect of PERK eIF2a Kinase Inhibitor against Toxoplasma gondii Antimicrobial Agents Chemotherapy Oct 24;62(11):e01442-18

Holmes MJ, Augusto LDS, Zhang M, Wek RC, Sullivan WJ Jr. (2017)

Translational Control in the Latency of Apicomplexan Parasites. Trends Parasitol. Sep 20. S1471-4922(17)30211-8. *Review.

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.

Indiana University

School of Medicine

Toxoplasmosis and the Stress Response