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Evaluation du potentiel thérapeutique d'un mannodendrimère anti-inflammatoire dans un modèle murin d'infection par Francisella tularensis

Abstract : Francisella tularensis is an intracellular Gram negative bacterium and the causative agent of tularemia. It is one of the most infectious agents known to date. Infection by the respiratory route leads to the deadly pulmonary form of tularemia. For these reasons, F. tularensis has been considered for years as a potential biological weapon. Pulmonary tularemia is characterized by an acute infection and a defect in immune responses. Particularly, the innate immune system plays a central role in F. tularensis infection and pathology. Macrophages, key cells of the innate immune system, are the main target for F. tularensis. This bacterium has evolved many strategies to escape host defenses that allow it to replicate within the cells and then disseminate into the whole organism. At this systemic stage, bacteria, along with alarm signals from infected cells, are recognized by innate immune receptors, triggering an inappropriate inflammatory response. The latter is characterized by a cytokine storm leading to a massive recruitment of immune cells, particularly neutrophils, in infected tissue. Tissue damages caused by this inflammation are a major cause of mortality associated with F. tularensis infections. Today, the treatment of tularemia is based on antibiotherapy. However, no specific symptoms can be assigned to pulmonary tularemia making its diagnosis difficult. This delays the administration of an appropriate antibiotiotherapy whose efficacy is therefore decreased. Thus, new therapeutic strategies are needed to replace or complement antibiotics. In this context, we investigated whether reducing the excessive inflammation induced by F. tularensis could be beneficial for the host and be considered as an adjunctive host- directed therapy. The aim of my work was to evaluate the anti-inflammatory properties and the therapeutic potential of mannodendrimer 3T (M3T), a synthetic coumpond designed in the team, in a mouse model of pulmonary infection by F. tularensis. M3T was previously designed to mimic the anti-inflammatory traits of a specific glycolipid from Mycobacterium tuberculosis. It was previously shown to inhibit the production of pro-inflammatory cytokines and neutrophils recruitment in a mouse model of LPS-induced pulmonary inflammation. Here, we used F. novicida as a surrogate for F. tularensis since it induces an identical inflammatory pathology. In vitro, M3T was found to inhibit the production of pro-inflammatory cytokines in human macrophages and dendritic cells infected by F. novicida. M3T modulates inflammatory response triggered by F. novicida via TLR2 most likely by the activation of a DC-SIGN-dependant pathway. In vivo, M3T was administered 6 h post-infection and then, daily for 3 days, by intraveinous injection and combined with a suboptimal antibiotic. This combination increases the survival rate of mice infected with F. novicida as compared to mice treated with antibiotic alone. M3T treatment has no impact on bacterial burden but seems to reduce tissue damages as observed by histological analyses of lungs, liver and spleen of infected mice. Altogether, our data demonstrate that M3T administration provides a therapeutic benefit in a mouse model of pulmonary infection by F. novicida. On a more general perspective our results suggest that targeting inflammation can be considered as an adjunctive treatment in acute pulmonary infections.
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Camille Robert. Evaluation du potentiel thérapeutique d'un mannodendrimère anti-inflammatoire dans un modèle murin d'infection par Francisella tularensis. Pharmacologie. Université Paul Sabatier - Toulouse III, 2017. Français. ⟨NNT : 2017TOU30299⟩. ⟨tel-01990416⟩

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