Immunopathologie et approche thérapeutique dans la Trypanosomose Africaine

Abstract : Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes have developped efficient mechanisms to escape the host immune response. New therapeutic options are needed for patients with HAT. Sterol 14α-demethylase (CYP51) is a potential drug target but its essentiality has not been studied in T. brucei. In a first study, we demonstrated its essentiality by RNA interference (CYP51RNAi) in vitro. CYP51RNAi induction caused morphological defects with multiflagellated cells, suggesting cytokinesis dysfunction. Additionally, the survival of CYP51RNAi infected-mice was improved, showing CYP51 RNAi effect on trypanosomal virulence. During infection with virulent strains, posaconazole-eflornithine and nifurtimox-eflornithine combinations showed similar improvement in mice survival. Thus, our results provide support for a CYP51 targeting based treatment in HAT. In a second work, we studied the innate host immune system characteristics in trypanosomiasis, as a severe immune dysregulation is present in HAT. To analyse the potential immunomodulatory activity of T. gambiense in human settings, we assess the effect of its secretome on dendritic cells (DCs) in vitro, using human monocyte-derived DCs. A significant inhibition of the LPS-induced maturation of DCs was observed with secretome. In line with this impairment, secretome down regulated cytokines production by LPS-activated DCs. TbKHC1, a kinesin heavy chain, is a component of the parasite secretome. We confirmed its role in parasitic escape to immune system by inducing arginase activity, in a murine model. Our results provide new information about the immune system characteristics during trypanosomiasis, which may help to uncover new therapeutic approachs in HAT.
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Frédéric-Antoine Dauchy. Immunopathologie et approche thérapeutique dans la Trypanosomose Africaine. Immunologie. Université de Bordeaux, 2016. Français. ⟨NNT : 2016BORD0390⟩. ⟨tel-02013380⟩

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