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Toxoplasma gondii modulates the mTORC1/2 and Mnk1/2 pathways and affects translation initiation in infected mammalian host cells

Leroux, Louis-Phillipe; Chaparro, Visnu; Larsson, Ola; Jaramillo, Maritza . Toxoplasma gondii modulates the mTORC1/2 and Mnk1/2 pathways and affects translation initiation in infected mammalian host cells In: 16e symposium annuel de parasitologie moléculaire du Québec, 6-7 juin 2016, Université McGill, Montréal, QC.

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Résumé

Toxoplasma gondii, the etiological agent of toxoplasmosis, is a ubiquitous obligate intracellular parasite. The infection remains usually asymptomatic, but reactivation of encysted parasites poses a threat to immunocompromised individuals (AIDS, chemotherapy). Also, congenital toxoplasmosis can lead to miscarriage or severe birth defects. In order to replicate, T. gondii scavenges nutrients from its host, targets numerous signaling pathways, and affects host cell transcription. Although these subversion strategies have been extensively studied, knowledge on translational control, specifically via the mTORC1/2 and Mnk1/2 pathways, by T. gondii is lacking. Here, we aim to determine whether the parasite affects these pathways to modulate mRNA translation in infected bone marrow-derived murine macrophages (BMMΦ) and BeWo cells, a human trophoblast cell line. Trophoblasts divide fetal and maternal tissues and are implicated in the vertical transmission of toxoplasmosis. BMMΦ and BeWo cultures were inoculated with either type I (virulent) or type II (avirulent) T. gondii strains, and by Western blotting we detected a sustained phosphorylation of the translation repressor 4E-BP1 (inactivation) and the ribosomal protein S6 (activation). In contrast, phosphorylation of S6K1, Mnk1, and the initiation factor eIF4E in BMMΦ was decreased, while it was maintained in infected BeWo cells. Polysomal profiling analyses revealed a higher polysome-to-monosome ratio in both cell types, indicative of an overall increase in the rate of translation upon infection. RNAseq analysis of the highly translated mRNAs (polysome-associated) and the total input material will allow us to distinguish transcripts regulated at the level of translation versus transcription. Ultimately, characterizing the translatome of T. gondii-infected cells will help identify metabolic and immune functions subverted through translational control.

Type de document: Document issu d'une conférence ou d'un atelier
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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 01 mai 2018 20:03
Dernière modification: 01 mai 2018 20:03
URI: http://espace.inrs.ca/id/eprint/7055

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