CDInfect

Systems Biology of C. difficile

The intestinal bacterium C. difficile causes life-threatening diseases, from diarrhea to severe inflammation of the intestine, which occur especially after antibiotic treatment. The most severe manifestation is a toxic megacolon, a very painful enlargement of the intestine, which leads to several thousand deaths per year in Germany. Until recently, there was no coordinated research on this important pathogen in Germany. With the support of the federal states of Lower Saxony and Mecklenburg-Vorpommern, a consortium for C. difficile research was founded in 2013. The consortium is very interdisciplinary and examines the role of bacterial adaptation mechanisms, the effect of toxins and the effect of the microbiome (the totality of all bacteria in the intestine) on C. difficile infections in different project areas.

The aim is a basic understanding of the organism in its environment, which can be used to develop therapies and diagnostics of C. difficile infections.

Project areas

In project area A (adaptation), infection relevant parameters including energy metabolism, biofilm formation, oxygen stress, pH, osmolarity, bile acids, antimicrobial peptides and protein modification will be investigated using joint transcriptomics, proteomics, metabolomics, interactomics and structural biology approaches. Bioinformatics-based data integration will help to identify the regulatory and metabolic networks of C. difficile underlying host adaptation, toxin production and successful infection. Conclusions will be validated in appropriate infection models (mouse, swine) and tested with representative clinical and environmental C. difficile isolates.

In project area B (toxins), the structure function-relationships of different C. difficile toxinotypes and their domains will be determined. The yet not understood proteomic and metabolic host responses to toxin exposure will be further investigated up to the host organelle level (mitochondria). Finally, the influence of bile acids, mucus and extracellular matrix on toxin function will be studied.

In project area C (microbiome), the interaction of C. difficile with the human/swine microbiome of the host is investigated using meta-transcriptome, -proteome and -metabolome profiling. Alterations in the microbiome and the intestinal barrier upon primary infection to cause recurrent infections will be approached. Comparative genome analyses of C. difficile from multiple natural sources (animals, soils, waters) will aid to identify underlying evolutionary forces, natural reservoirs, and transmission pathways. The genomic co-evolution of C. difficile and the microbiome will be elucidated.