Inhibitors of eIF2α dephosphorylation slow replication and stabilize latency in Toxoplasma gondii

Antimicrob Agents Chemother. 2013 Feb 4. [Epub ahead of print]

Inhibitors of eIF2α dephosphorylation slow replication and stabilize latency in Toxoplasma gondii

Konrad C, Queener SF, Wek RC, Sullivan WJ Jr.

Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Toxoplasma gondii is an obligate intracellular parasite that permanently infects warm-blooded vertebrates through its ability to convert into a latent tissue cyst form. The latent form (bradyzoite) can reinitiate a life-threatening acute infection if host immunity wanes, most commonly in AIDS or organ transplant patients. We have previously shown that bradyzoite development is accompanied by phosphorylation of the parasite eukaryotic initiation factor-2 alpha subunit (eIF2α), which dampens global protein synthesis and reprograms gene expression. In this study, we analyzed the activities of two specific inhibitors of eIF2α dephosphorylation, salubrinal (SAL) and guanabenz (GA). We establish that these drugs are able to inhibit the dephosphorylation of Toxoplasma eIF2α. Our results show that SAL and GA reduce tachyzoite replication in vitro and in vivo. Furthermore, both drugs induce bradyzoite formation and inhibit the reactivation of latent bradyzoites in vitro. To address whether the antiparasitic activities of SAL and GA involve host eIF2α phosphorylation, we infected mutant MEF cells incapable of phosphorylating eIF2α, which had no impact on the efficacy of SAL and GA against Toxoplasma infection. Our findings suggest that SAL and GA may serve as potential new drugs for the treatment of acute and chronic toxoplasmosis.

PMID: 23380722 [PubMed - as supplied by publisher]