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Modulation de l’activité des cellules dendritiques par la réponse UPR induite lors de l’infection à Toxoplasma gondii

Abstract : The intracellular parasite Toxoplasma gondii (T. gondii) is one of the most common zoonotic pathogen invading all animals, including humans. In healthy individuals, type II parasite persists in cysts in the central nervous system leading to severe mental disorders and increasing the risk of developing neuro degenerative diseases. The control of chronic toxoplasmosis relies on dendritic cells (DCs) functions that activate the IL-12- induced Tcell IFN-g-derived response. In order to survive, T. gondii secretes an arsenal of virulencefactors that modulate host immune responses; however the interplay between DCs andT. gondii has been poorly explored. Recent studies highlighted the intricate molecularcross-talk between the Unfolded Protein Response (UPR) and the innate pathways. TheUPR response is a cytoprotective response induced during a cellular stress triggered byan imbalance in protein and lipid homeostasis, but also during intracellular pathogen infection.So far, nothing is known about the influence of T. gondii infection on the UPR.We hypothesized that T. gondii induction of the UPR could modulate the antigenic presentationability and cytokine secretion of DCs, thereby impacting parasite disseminationand persistence. Using, Bone-Marrow-derived DC (BMDCs) and mice deficient for the ERsensor IRE1a and the transcription factor XBP1, we examined the impact of the UPR onDC responses and T cell activation. Our results demonstrated that T. gondii infectionactivates the IRE1a arm of the UPR in BMDCs in a MyD88 dependent manner, therebyinducing a unique set of secreted pro-inflammatory cytokines. We also demonstrated thatthis pathway regulates MHC-I presentation of secreted parasite antigens. In infected mice,we found that the IRE1a/XBP1s pathway is specifically activated in splenic cDC1s, regulatesT CD8+ cell responses and thus, the IFN-g production. In addition, IRE1a/XBP1deficient mice do not control parasite proliferation and succomb during the acute phaseof the infection. Therefore, our work revealed an essential protective role of the IRE1abranch of the UPR in DCs to fight T. gondii infection.
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Anaïs Poncet. Modulation de l’activité des cellules dendritiques par la réponse UPR induite lors de l’infection à Toxoplasma gondii. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2019. Français. ⟨NNT : 2019LIL2S038⟩. ⟨tel-02923628⟩

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