Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival.

Louis-Philippe Leroux,Visnu Chaparro,Maritza Jaramillo

doi:10.3389/fcimb.2020.00488

Louis-Philippe Leroux, Visnu Chaparro + Show 1 more

Open Access

https://doi.org/10.3389/fcimb.2020.00488

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Abstract

The obligate intracellular parasite Toxoplasma gondii reprograms host gene expression through multiple mechanisms that promote infection, including the up-regulation of mTOR-dependent host mRNA translation. In addition to the mTOR-4E-BP1/2 axis, MAPK-interacting kinases 1 and 2 (MNK1/2) control the activity of the mRNA cap-binding protein eIF4E. Herein, we show that T. gondii inhibits the phosphorylation of MNK1/2 and their downstream target eIF4E in murine and human macrophages. Exposure to soluble T. gondii antigens (STAg) failed to fully recapitulate this phenotype indicating the requirement of live infection. Treatment with okadaic acid, a potent phosphatase inhibitor, restored phosphorylation of MNK1/2 and eIF4E regardless of infection. T. gondii replication was higher in macrophages isolated from mice mutated at the residue where eIF4E is phosphorylated (eIF4E S209A knock-in) than in wild-type (WT) control cells despite no differences in infection rates. Similarly, parasitemia in the mesenteric lymph nodes and spleen, as well as brain cyst burden were significantly augmented in infected eIF4E S209A knock-in mice compared to their WT counterparts. Of note, mutant mice were more susceptible to acute toxoplasmosis and displayed exacerbated levels of IFNγ. In all, these data suggest that the MNK1/2-eIF4E axis is required to control T. gondii infection and that its inactivation represents a strategy exploited by the parasite to promote its survival.

Highlights

Toxoplasma gondii (T. gondii), the etiologic agent of toxoplasmosis, is an intracellular protozoan parasite that infects a wide variety of vertebrate hosts, including humans and mice (Innes et al, 2019)
T. gondii Inhibits Host MAPK-interacting kinases 1 and 2 (MNK1/2) and eukaryotic initiation factor 4E (eIF4E) Phosphorylation and Disrupts Upstream Signaling in Infected Macrophages
The induction of ERK1/2 phosphorylation by ME49, and the inhibition of MNK1/2 and eIF4E phosphorylation by both RH and ME49 followed an MOI-dependent trend whereby the respective phenotypes were increasingly pronounced as the parasite-to-host ratio increased (Supplementary Figure 1)

Summary

Introduction

Toxoplasma gondii (T. gondii), the etiologic agent of toxoplasmosis, is an intracellular protozoan parasite that infects a wide variety of vertebrate hosts, including humans and mice (Innes et al, 2019). T. gondii is able to invade any nucleated cell and usurps host cell organelles and nutrients in order to replicate within its parasitophorous vacuole (Clough and Frickel, 2017). The parasite targets signaling pathways and host gene expression to subvert immune responses and establish a favorable. Repression of Host MNK1/2-eIF4E Signaling by Toxoplasma gondii environment (Hakimi et al, 2017; Blume and Seeber, 2018; Delgado Betancourt et al, 2019). Among the different strategies employed by the parasite, it was shown that T. gondii is able to fine-tune host gene expression post-transcriptionally in part through perturbations in translational efficiency of host mRNAs (Leroux et al, 2018)

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