Contributions à l’étude de l’échappement des leptospires au système immunitaire : mise en évidence chez la souris de la colonisation rénale chronique à l’aide de leptospires bioluminescents, et rôle de la lipoprotéine LipL21 dans l’échappement du peptidoglycane à la reconnaissance par les récepteurs Nods

Abstract : Leptospirosis is a widespread zoonosis caused by the bacterium Leptospira interrogans (L interrogans). In humans, infection with L. interrogans can cause either a mild disease or in more severe cases, multi-organ failure potentially leading to death. Leptospires escape from the innate immune response by evading detection by Toll-like receptors (TLR). Indeed, the lipopolysaccharide (LPS) outer membrane component of Leptospira is atypical as, unlike most Gram-negative bacteria, it is not recognized by human TLR4. However, leptospiral LPS is recognized by murine TLR4, facilitating clearance of leptospires in mice. During my doctoral thesis, we revealed a new mechanism of leptospiral escape from recognition by Nod1 and Nod2 innate immune receptors. We have shown that a specific leptospiral outer membrane lipoprotein, LipL21, impairs muropeptides digestion and therefore avoids activation of Nod1 and Nod2 receptor-mediated pathways. This constitutes a new strategy of bacterial escape from Nod1 and Nod2 receptor recognition. Indeed, until now, only modification of the peptidoglycan sugar or peptide side-chain chemistry was shown to participate in evasion of Nod receptor recognition. Furthermore, through the construction of a bioluminescent pathogenic Leptospira strain, we were able to develop a new murine model to study acute and chronic leptospirosis. We found that, after the acute phase of leptospirosis, infected mice become asymptomatic, but exhibit chronic carriage of Leptospira in the kidneys, as in rat models of leptospirosis. This biphasic leptospirosis model allows us to highlight leptospiral renal colonization as a stealth escape strategy from the blood defenses and antibiotics. Our results reveal two new mechanisms that contribute to leptospiral escape from the host immune system: on one hand, LipL21 lipoprotein plays a role by facilitating evasion of peptidoglycan recognition through Nod1 and Nod2 receptors, and on the other hand, leptospires escape from host defenses by colonising a renal niche in mice. Together, these findings provide novel insight into the ability of Leptospira to cause serious and chronic morbidity in humans.
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Gwenn Ratet. Contributions à l’étude de l’échappement des leptospires au système immunitaire : mise en évidence chez la souris de la colonisation rénale chronique à l’aide de leptospires bioluminescents, et rôle de la lipoprotéine LipL21 dans l’échappement du peptidoglycane à la reconnaissance par les récepteurs Nods. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2015. Français. ⟨NNT : 2015USPCB059⟩. ⟨tel-01499843⟩

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