Genomic and transcriptomic study of high potential virulence strains of Clostridium difficile. Clostridioides difficile E23

Clostridium difficile-associated diarrhoea (CDAD) is currently the most frequently occurring nosocomial infection in many European hospitals. Clostridium difficile induces severe diarrhoea in patients with compromised normal gut flora due to antibiotic usage and/or underlying disease conditions. Clinical severity ranges from mild, self-limiting diarrhoea to the potentially fatal pseudomembranous colitis (PMC). The incidence and severity of CDAD has shown a dramatic increase since 2003. It can be partially explained by the emergence of a highly virulent type (ribotype 027) throughout North America and Europe. The two large toxins, toxin A and B, produced by the pathogenic Clostridium difficile strains have been recognized as the main virulence factors. But studies of genotypes with increased virulence have revealed that in addition to host factors (immunity…), other bacterial virulence factors have to be involved. Most of the current studies on increased virulence have currently concentrated to type 027. However, we assume that other Clostridium difficile strains which are at present less numerous and only occasionally associated with severe cases and outbreaks, might have an increased virulence potential and could represent the future epidemic types. The objectives of this project are to use genomic approaches to define Clostridium difficile groups with increased virulence potential and subsequently analyze their genomic characteristics in terms of the presence of known and new virulence factors, regulation of their expression and genomic heterogeneity. By using genomic and transcriptomic approaches, we will compare genomic differences and differences in gene expression among the genotypes associated with increased virulence and control groups from asymptomatic carriers or mild cases. Genes potentially associated with hypervirulence characters identified will be tested further for their role in the pathogenesis process and/or in the interaction with the host by constructing knockout mutants and challenged in the animal models.