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Caractérisation de facteurs de virulence impliquant les systèmes de sécrétion bactériens

Abstract : Pseudomonas aeruginosa is the causative agent of nosocomial infections. Those infections are a real threat to public health, considering that P. aeruginosa is a member of the ESKAPE pathogens family. Those pathogens developed numerous antibiotic resistance mechanisms that allow them to escape the lethality of common treatments. More than just resistant, P. aeruginosa is able to make use of several virulence factors, and among them, the type V secretion system, which is the main subject of my PhD.A new virulent P. aeruginosa strain was discovered in Grenoble University Hospital several years ago. This strain lacked the virulence factors of common studied cytotoxic strains but, still displayed high toxicity. This was related to the expression of two proteins, ExlB and ExlA, that are part of the T5SSb and display a complete new mechanism of action (no protein homologs are found). The ExlA toxin is able to form pores in the eukaryotic cell membrane leading to their death. The aim of my PhD was to understand on a molecular level the mechanism of ExlA toxicity.To decipher the activity of this toxin, we divided it in two domains, studied separately. Using NMR, SEC-MALLS, liposome floating assay, SAXS and AFM techniques, we were able to prove that the C-terminal domain of ExlA was a « molten globule » in solution and was able to form holes in reconstituted lipid bilayers. This domain seems to be the key to lipid interaction by the whole protein. Additional in vivo studies of the N-terminal domain and on full-length ExlA allowed us to propose a putative model of the mechanism of this novel toxin.
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Quentin Bertrand. Caractérisation de facteurs de virulence impliquant les systèmes de sécrétion bactériens. Biologie structurale [q-bio.BM]. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAV058⟩. ⟨tel-02957681⟩

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