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Dissecting the molecular mechanisms involved in dysregulated host cell responses during toxoplasmosis

Díez, Andrés Felipe, Leroux, Louis-Phillipe, Chagneau, Sophie, Vaillancourt, Cathy et Jaramillo, Maritza . Dissecting the molecular mechanisms involved in dysregulated host cell responses during toxoplasmosis In: Colloque en ligne du Centre d’Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois, 23 novembre 2020, virtuel.

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Résumé

The intracellular protozoan parasite Toxoplasma gondii is the etiological agent of toxoplasmosis, a life-threatening infection in immunocompromised patients. Moreover, T. gondii causes congenital toxoplasmosis resulting in severe birth defects or miscarriage. Due to the lack of efficient vaccines and non-teratogenic treatments, it is of imperative to better understand the molecular mechanisms underlying the interactions between T. gondii and the host. Forkhead-box-O3a (FOXO3a) is a transcription factor that mediates essential cellular processes that include proliferation, resistance to oxidative stress, inflammation, apoptosis, and autophagy. Accordingly, dysregulated FOXO3a activity has been reported in multiple pathologies; however, the involvement of FOXO3a during toxoplasmosis has yet to be investigated.We demonstrated that T. gondii represses translation of Foxo3a mRNA and thereby reduces FOXO3a protein synthesis in the host cell. Hence, we postulate that alteration of transcriptional programs downstream of FOXO3a contribute to host cell dysfunction during toxoplasmosis. To address this, we initially focused on fibroblasts as they are one of the most permissive cell populations to T. gondii infection. Subcellular fractionation experiments combined with immunofluorescence microscopy approaches showed a reduction in nuclear FOXO3a levels in a human foreskin fibroblast (HFF) cell line infected with T. gondii. In line with these data, mRNA and protein expression of FOXO3a transcriptional target genes p130 (cell cycle), Beclin-1 (autophagy), and catalase (oxidative stress) were reduced. Ongoing experiments using chemical compounds and forward-genetics approaches to modulate FOXO3a expression, localization and/or activity in fibroblasts will provide further insight on the role of dysregulated FOXO3a-dependent transcriptional programs in pathology associated with toxoplasmosis.

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: 14 juill. 2021 15:58
Dernière modification: 14 juill. 2021 15:58
URI: https://espace.inrs.ca/id/eprint/11803

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