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Dysregulation of FOXO3a-dependent transcriptional programs and cellular functions during Toxoplasma gondii Infection

Diez, Andrés Felipe, Leroux, Louis-Phillipe, Chagneau, Sophie, Vaillancourt, Cathy et Jaramillo, Maritza . Dysregulation of FOXO3a-dependent transcriptional programs and cellular functions during Toxoplasma gondii Infection In: 13e symposium du Réseau Québécois en reproduction, 9-11 novembre 2020, virtuel.

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Forkhead box O3a (FOXO3a) is a transcription factor that mediates essential cellular processes that include proliferation, resistance to oxidative stress, inflammation, apoptosis, and endometrial decidualization. Accordingly, reduced FOXO3a levels in the uterus are associated with spontaneous abortion. Toxoplasma gondii (T. gondii) is the etiological agent of congenital toxoplasmosis, a parasitic infection that can lead to miscarriage and premature births; however, the molecular underpinnings of disease pathogenesis remain poorly defined. We demonstrated that T. gondii represses translation of Foxo3a mRNA and thereby reduces FOXO3a protein synthesis in the host cell. This phenotype was confirmed in several cell types present in the villous stroma, namely trophoblasts, macrophages, and fibroblasts. Hence, we postulate that alteration of transcriptional programs downstream of FOXO3a contribute to placental dysfunction during congenital toxoplasmosis. To address this, we initially focused on fibroblasts as they are the most permissive cell type to T. gondii infection in the villous stroma. Subcellular fractionation experiments combined with image flow cytometry 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 in T. gondii-infected HFF. Ongoing experiments using chemical compounds and forward-genetics approaches to modulate FOXO3a expression, localization and/or activity in fibroblasts and other placental populations will provide further insight on the role of dysregulated FOXO3a-dependent transcriptional programs in placental pathology associated with congenital toxoplasmosis.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche scientifique page 49 du document
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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 14 juill. 2021 15:56
Dernière modification: 14 juill. 2021 15:56
URI: https://espace.inrs.ca/id/eprint/11811

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