Translational Control in the Latency of Apicomplexan Parasites

Abstract

Apicomplexan parasites Toxoplasma gondii and Plasmodium spp. use latent stages to persist in the host, facilitate transmission, and thwart treatment of infected patients. Therefore, it is important to understand the processes driving parasite differentiation to and from quiescent stages. Here, we discuss how a family of protein kinases that phosphorylate the eukaryotic initiation factor-2 (eIF2) function in translational control and drive differentiation. This translational control culminates in reprogramming of the transcriptome to facilitate parasite transition towards latency. We also discuss how eIF2 phosphorylation contributes to the maintenance of latency and provides a crucial role in the timing of reactivation of latent parasites towards proliferative stages.

Keywords: Plasmodium; Toxoplasma; eIF2; latency; translational control.

Figure 1. Proliferative and latent stages in Toxoplasma gondii and Plasmodium spp

Apicomplexans utilize latency to maintain viability and infectivity in response to different signals such as exposure to the extracellular environment, pH variation, alterations in temperature, the host immune response, oxidative stress, nutrient deprivation, and exposure to chemotherapeutics. In response to these environmental changes, the translational initiation factor eIF2 is phosphorylated, activating the gene regulatory regimen known as the integrated stress response that directs the parasites to modify their metabolism and differentiate into latent forms. Upon transmission, changes in the parasite’s environment occur and eIF2 phosphorylation is alleviated, signaling developmental progression. Arrows represent differentiation between latent and proliferative forms. Parasites are not in scale.

Figure 2. Schematic of eIF2 kinase architecture from Toxoplasma gondii and Plasmodium falciparum

The parasite eIF2 kinases are illustrated to scale with the amino acid length indicated below each. Each of the eIF2 kinases encode a single protein kinase domain represented by a red box. The lengths of the kinase domains are variable among the eIF2 kinases because of the different sizes of the insert sequences (black hatching) that are hallmark features of the eIF2 kinase families. Both organisms encode a PERK-like kinase with a predicted transmembrane domain (black line). The GCN2-like kinases each contain a HisRS-related domain (blue box) that binds uncharged tRNAs which are responsible for kinase activation. IF2K-D also has an RWD domain (yellow box) that binds the regulatory protein GCN1. The signals that activate each eIF2 kinase and their cellular locations are listed to the right. ER, endoplasmic reticulum; a.a., amino acid.