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Caractérisation des propriétés anti-infectieuses de la flagelline, agoniste du Toll-like receptor 5

Abstract : With its ability to sense micro-organisms and to induce a rapid defense against infections, innate immunity represents the first line of host’s defense. The innate immune response is triggered by universal and conserved microbial molecular patterns recognized by innate receptors including the Toll-like receptors (TLRs). Activation of these receptors induces local inflammation and antimicrobial response against pathogens. These biological properties have allowed considering the use of TLR as anti-infective therapeutic target. In this context it has been shown that flagellin, the major component of bacterial flagella and the agonist of TLR5, had anti-infectious properties. It was shown that flagellin induces a strong production by innate lymphoid cells of IL-22, a cytokine involved in the protection of mucosa. Furthermore, the strong expression of TLR5 by epithelial cells suggests a role for these cells in the anti-infectious properties of flagellin. However, the molecular and cellular mechanisms responsible for the antimicrobial effects of the TLR5 agonist remained to be defined.In this thesis, we studied the anti-infectious properties of flagellin in two infectious murine models. We first showed that systemic administration of flagellin, prior to infectious challenge, protect against an intestinal infection with Yersinia pseudotuberculosis. The protection induced by flagellin is observable upon infection by mucosal route but is absent during a challenge by the systemic route, thus demonstrating the role of the mucosa for the protection. The anti-bacterial effect in this model is dependent on the expression of TLR5 and independent of the innate lymphoid cells’ IL-22 production. This study suggests a novel mechanism of flagellin-mediated protection, independent of the IL-22.We also analyzed the anti-infectious abilities of flagellin in a murine model of respiratory infection by Streptococcus pneumoniae. In particular, we showed that flagellin could be used in therapy when combined to an antibiotic. Indeed, the combination of amoxicillin or co-trimoxazole with flagellin protected mice infected with a lethal dose of S. pneumoniae compared to antibiotic standalone. The effectiveness of this therapy was dependent on the activation of TLR5 and was associated with pulmonary infiltration of neutrophils. This combinatory treatment also improved the protection in a model of post-influenza pneumococcal superinfection. These results show that the combination of TLR5 agonist / antibiotic ameliorates pulmonary anti-infectious response and allow to consider new antibacterial strategies against infections when antibiotics reach their limits (nosocomial infections, multiresistant bacteria ...).
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Rémi Porte. Caractérisation des propriétés anti-infectieuses de la flagelline, agoniste du Toll-like receptor 5. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2015. Français. ⟨NNT : 2015LIL2S065⟩. ⟨tel-01673791⟩

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