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

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...

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Autores principales: Leroux, Louis-Philippe, Chaparro, Visnu, Jaramillo, Maritza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509071/
https://www.ncbi.nlm.nih.gov/pubmed/33014898
http://dx.doi.org/10.3389/fcimb.2020.00488
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author Leroux, Louis-Philippe
Chaparro, Visnu
Jaramillo, Maritza
author_facet Leroux, Louis-Philippe
Chaparro, Visnu
Jaramillo, Maritza
author_sort Leroux, Louis-Philippe
collection PubMed
description 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.
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spelling pubmed-75090712020-10-02 Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival Leroux, Louis-Philippe Chaparro, Visnu Jaramillo, Maritza Front Cell Infect Microbiol Cellular and Infection Microbiology 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. Frontiers Media S.A. 2020-09-09 /pmc/articles/PMC7509071/ /pubmed/33014898 http://dx.doi.org/10.3389/fcimb.2020.00488 Text en Copyright © 2020 Leroux, Chaparro and Jaramillo. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Leroux, Louis-Philippe
Chaparro, Visnu
Jaramillo, Maritza
Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival
title Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival
title_full Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival
title_fullStr Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival
title_full_unstemmed Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival
title_short Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival
title_sort infection by the protozoan parasite toxoplasma gondii inhibits host mnk1/2-eif4e axis to promote its survival
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509071/
https://www.ncbi.nlm.nih.gov/pubmed/33014898
http://dx.doi.org/10.3389/fcimb.2020.00488
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