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Mécanismes moléculaires impliqués dans l'adaptation de Francisella tularensis à sa niche intracellulaire

Abstract : Francisella tularensis is the etiological agent responsible for tularemia, an endemo-epidemic zoonosis in the northern hemisphere, capable of infecting a large number of animal species (mammals, birds, insects, ...) and potentially highly pathogenic for the man. This pathology, still poorly known, has very polymorphous manifestations, ranging from mild to deadly lung forms. During mammalian infection, Francisella multiplies mainly within macrophage cells. However, during its systemic dissemination, it is able to infect many other cell types, including non-phagocytic (epithelial, hepatocytes, ...). For this, Francisella has developed mechanisms to escape lysis in the phagosome and to multiply in the cytoplasm of infected cells where it gets some essential elements for its growth. In a first part, we focused on the metabolic adaptation of Francisella during its intracellular cycle and in particular the role of a key enzyme of Glycolysis / Gluconeogenesis, fructose-1,6-biphosphate aldolase (FBA). Beyond its housekeeping role in metabolism, we demonstrate that FBA is important for bacterial multiplication in macrophages in the presence of gluconeogenic substrates. In addition, we highlight a direct role of this metabolic enzyme in the regulation of transcription of the genes katG and rpoA, coding respectively for catalase and a subunit of RNA polymerase. We propose a model in which FBA participates in the control of host redox homeostasis and inflammatory immune response. In a second part, we were interested in Francisella's type VI secretion system (T6SS). Many Gram-negative bacteria use T6SS to translocate effector proteins into eukaryotic or prokaryotic cells. Francisella has a non-canonical T6SS encoded on the pathogenicity FPI island that is essential for phagosome release and allows the bacterium to multiply in the cytosol of the host cell. Using a global phosphoproteomic approach in novicida subspecies, we identified a unique phosphorylation site on IglB tyrosine 139, a key component of the contractile sheath of T6SS. We demonstrate that the phosphorylation status of IglB plays an important role in the assembly of a functional T6SS. We propose that this post-translational modification of the major component of the cladding may constitute a regulation mechanism for modulating the assembly / disassembly dynamics of the SST6.
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Jason Ziveri. Mécanismes moléculaires impliqués dans l'adaptation de Francisella tularensis à sa niche intracellulaire. Microbiologie et Parasitologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB055⟩. ⟨tel-02509816⟩



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