Toxoplasma gondii is an obligate intracellular parasite that has infected one third of the population. Upon infection of warm-blooded vertebrates, the replicating form of the parasite (tachyzoite) converts into a latent form (bradyzoite) present in tissue cysts. During immune deficiency, bradyzoites can reconvert into tachyzoites and cause life-threatening toxoplasmosis. We previously reported that translational control through phosphorylation of the α subunit of T. gondii eIF2 (TgIF2α) is a critical component of the parasite stress response. Diverse stresses can induce the conversion of tachyzoites to bradyzoites, including those disrupting the parasite's endoplasmic reticulum (ER stress). Toxoplasma possesses four eIF2 kinases, one of which (TgIF2K-A) localizes to the parasite ER analogous to PERK, the eIF2 kinase that responds to ER stress in mammalian cells. Here, we investigated the effects of a PERK inhibitor (PERKi) on Toxoplasma. Our results show that the PERKi GSK2606414 blocks the enzymatic activity of TgIF2K-A and reduces TgIF2α phosphorylation specifically in response to ER stress. PERKi also significantly impedes multiple steps of the tachyzoite lytic cycle and sharply lowers the frequency of bradyzoite differentiation in vitro. Pretreatment of host cells with PERKi prior to infection does not affect parasite infectivity, and PERKi still impairs parasite replication in host cells lacking PERK. In mice, PERKi confers modest protection from a lethal dose of Toxoplasma. Our findings represent the first pharmacological evidence supporting TgIF2K-A as an attractive new target for the treatment of toxoplasmosis.
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