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Leishmania modulates phagosome fonctions by altering certain SNAREs in a GP63-dependent pathway


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Moradin, Neda (2013). Leishmania modulates phagosome fonctions by altering certain SNAREs in a GP63-dependent pathway Mémoire. Québec, Université du Québec, Institut National de la Recherche Scientifique, Maîtrise en virologie et immunologie, 280 p.

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Leishmania is the parasite responsible for the leishrnaniases. Like severa! other intracellular pathogens, they evolved multiple strategies to escape the immune system. In macrophages, phagosomes mature through sequential fusion and fission events with various compartments of the endocytic pathway. This process is interrupted by Leishmania promastigotes when they block aquisition of microbicidal molecules from late endosomes and lysosomes while amastigotes-harboring vacuoles are hybrid compartments composed of both endoplasmic reticulum and endocytic pathway components. The N-ethylmaleimide sensitive factor (NSF) attachrnent receptor proteins (SNAREs) act in intracellular trafficking pathways such as phagolysosome biogenesis. Inhibition of phagosome remodeling through different virulenece factors including LPG and GP63 is one of the most important strategies by Leishmania to survive and replicate in host cells. In the first project, we showed that Leishmania cleaves V AMP8 protein which is one of the vesicular SNAREs on phagosome membranes. We also demonstrated that V AMP8 plays a key role in cross-presentation, which is inhibited by Leishmania through GP63-dependent cleavage of V AMP8. It had been already shown that gp91phox is one of the crucial subunits in the NADPH oxidase complex that regulates cross-presentation in dendritic cells. We found that V AMP8 is necessary for the recruitment of gp91plwx on the phagosome membrane whereby the NADPH oxidase regulates cross-presentation in dendritic cells. In the second project, we investigated the effect of Leishmania on other SNAREs. lt is already known that Sec22b is a regulator for cross-presentation and in this study we showed that Sec22b (ER-SNARE) is excluded from phagosomes harbouring Leishmania in a GP63- dependent manner. Since Sec22b is not cleaved by GP63, this exclusion is likely to be due to the action of GP63 on cognate proteins in the Sec22b complex. We also showed that sorne Sec22b interacting proteins such as syntaxin 4, -5 and SNAP23 are cleaved by GP63 and play a bactericidal role in macrophages. Altogether, we show novel mechanisms used by Leishmania to escape the immune system through the impairment of cross-presentation by degrading key regulators of vesicular trafficking. Also, we show that Leishmania cleaves SN AREs that regulate the bactericidal ability of the macrophage.

Type de document: Thèse Mémoire
Directeur de mémoire/thèse: Descoteaux, Albert
Mots-clés libres: phagocytose
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 06 nov. 2015 16:44
Dernière modification: 09 nov. 2015 20:03
URI: https://espace.inrs.ca/id/eprint/2779

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