Rôle et mécanismes moléculaires d'action des lipides de l'enveloppe de Mycobacterium tuberculosis dans la virulence

Abstract : Mycobacterium tuberculosis is the bacterium responsible for tuberculosis (TB), a severe respiratory disease. TB is a major public health threat; one third of the world's population is latently infected by M. tuberculosis, and the emergence of antibiotic-resistant forms of TB confirms that there is a need to develop new therapeutic approaches to control the spread of TB. However, in order to attain that goal, it is crucial to decipher the infectious mechanisms of M. tuberculosis. Research in the team of C. Guilhot focuses on lipids from the envelope of M. tuberculosis which are involved in virulence, in particular those implicated in the interaction of the bacteria with host macrophages. One of these lipids stands out for its crucial role in this interaction: Phthiocerol Dimycocerosate (DIM). Despite its importance, the molecular mechanism of action of DIM is still unknown. The objectives of my PhD were 1) to study the role of DIM in the intracellular trafficking of M. tuberculosis in macrophages, and 2) to decipher the molecular mechanism of action of DIM. By a combination of biological and biophysical techniques, we showed that DIM contributes to phagosomal rupture and induction of apoptosis in macrophages infected with M. tuberculosis, in collaboration with another major virulence factor: ESAT-6. At the molecular level, we confirmed that DIM is transferred to the membrane of the macrophage on contact with M. tuberculosis and induces a local membrane rigidification around the point of contact with the bacterium. We observed that DIM incorporated in membranes is able to promote the membranolytic activity of ESAT-6, and other yet unidentified bacterial factor(s). DIM has a pleiotropic role in the interaction between M. tuberculosis and macrophages, presumably through alterations of the membrane's biophysical properties that influence the activity of membrane effectors from both the bacteria and the host. Thus, this work paves the way for the study of the mechanisms of action of other virulence lipids, some of which could also be inserted in the macrophage membrane.
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Jacques Augenstreich. Rôle et mécanismes moléculaires d'action des lipides de l'enveloppe de Mycobacterium tuberculosis dans la virulence. Bactériologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30111⟩. ⟨tel-02306983⟩

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