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Virulence des Escherichia coli entérohémmoragiques : rôle central du monoxyde d'azote dans le devenir de l'infection et identification de nouveaux déterminants impliqués dans l'adaptation du pathogène à l'envirronement digestif

Abstract : Enterohemorrhagic Escherichia coli (EHEC) are a major public health concern. Indeed, these pathogens are responsible for thousands of food-borne illness cases worldwide every year and can lead to serious complications, including kidney damages in young children and brain damages in the elderly. Currently, the main issue is the limited number of available therapeutic treatments since antibiotic therapy can promote the development of infection-related complications. Therefore, it appears essential and topical to identify bacterial factors associated with EHEC virulence and to understand the interactions occurring between the pathogen and the host, in order to develop new anti-infective strategies. The first objective of this thesis was to identify new bacterial factors potentially involved in the infectious process. Application of the RIVET technology to the reference strain O157:H7 EDL933 revealed 31 genes specifically induced during mouse infection. Characterization of these genes showed that some of them encode niche factors potentially involved in the adaptation of EHEC to the intestinal environment, therefore contributing to virulence. The second aim of this thesis was to characterize in vivo the response of EHEC to nitric oxide (NO), a mediator of the host’s immune response, and thus assess the protective role of NO against EHEC infection in a mouse model. By using a NO-sensing reporter EHEC strain, we demonstrated that NO is produced by the host at the early stages of infection and this NO limits adhesion of the pathogen to the colonic mucosa. On the other hand, we also showed that NO is detrimental to the host since it promotes the production of Shigatoxins (Stx), which is the major EHEC virulence factor, and leads to the development of renal dysfunction. Finally, we showed that the NO reductase NorVW is important for the virulence of some, but not all, EHEC strains. Inactivation of the norVW operon in strain O157:H7 620 reduces the ability of the pathogen to efficiently colonize the digestive tract and to produce Stx. However, this observation is strain-specific and this suggests that EHEC response to nitrosative stress during infection is complex and probably multifactorial. This work contributes to a better understanding of the EHEC infectious process, an essential step for the development of future anti-infective strategies.
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Marion Gardette. Virulence des Escherichia coli entérohémmoragiques : rôle central du monoxyde d'azote dans le devenir de l'infection et identification de nouveaux déterminants impliqués dans l'adaptation du pathogène à l'envirronement digestif. Bactériologie. Université Clermont Auvergne, 2019. Français. ⟨NNT : 2019CLFAC075⟩. ⟨tel-02954350⟩

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