Introduction

Clostridium difficilea gram-positive, anaerobic, spore forming bacterium,is responsible for 25% of all cases of antibiotic-associated diarrhoea and for the majority of the pseudomembranous colitis. It is the main enteropathogen bacterium isolated in nosocomial diarrhoea of adults. Since 2003, highly pathogen strains have emerged and the rate and the severity of C difficileinfections have dramatically increased. Many virulence factors seem to be involved during the gut colonization and the process of C difficileinfection. However, the production of two toxins (TcdA and TcdB) plays a major role in the pathogenicity of this bacterium.

- Control of C. difficiletoxin synthesis and secretion: Characterization of the molecular mechanisms controlling the timing of toxin synthesis, via the relation between a sigma - anti sigma factors (TcdR/TcdC), and of the role of TcdE holin-like protein in the toxin release by a phage-like system.

- Global regulation of C. difficiletoxin production in response to environmental signals: Decipheringthe molecular mechanisms of the control of toxin synthesis by carbon catabolite repression and by the cysteine involving the global regulator, CcpA, and regulators sensing cysteine availability, respectively.

- The regulatory network of transition phase controlling C. difficiletoxin production. Analysis of the role of three global regulators playing a key role in the transition phase: the sigma factor, SigH, the response regulator of a two-component system, Spo0A and the repressor SinR, in the physiology of C. difficile, the spores production (the form of dissemination), the motility, the formation of biofilms, the toxin synthesis and colonization factors.

-C. difficilepathogenesis process by analysis a genome-wide temporal expression in host:Understanding the first steps of gut colonizationby C. difficileand the relationship with toxin production by comparing gene expression in vitroand in vivo during infection in an axenic mouse model.

- Genetic relatedness of C. difficilestrains associated to an increased virulence potential:Analysisof the genomic characteristics of selected C. difficile strains with increased virulence potential by genomic and transcriptomic comparisons andto look for the genomic heterogeneity, the presence of known and new virulence factors and the regulation of their expression.

-Connections between sulfur metabolism and pathogenesis in firmicutes:Establishing the role of the main regulatory system of sulfur metabolism (CymR/CysK) in virulence and adaptation of Staphylococcus aureus. The regulatory mechanisms linking cysteine metabolism with the regulon of virulence in Clostridium perfringensand C. difficile were also investigated.

Keywords: Clostridia, epidemic strains, anaerobia, toxins, gut colonization, metabolism, regulation, sigma anti-sigma factors

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