The Gram-positive anaerobic bacterium Clostridioides difficile (formerly Clostridium difficile) is becoming a leading cause of detrimental bacterial infections in developed countries. The bacterium is responsible for the majority of antibiotic treatment-associated diarrhoeas. Approximately 453,000 cases of C. difficile infections per year are reported in the USA, with about 29,000 patients dying from it, whereas the prevalence in Germany for unknown reasons is about a fifth of that in the US. Estimated health costs are over $1.5 billion. Overall, the rate of C. difficile infections is growing to replace antibiotic-resistant Staphylococcus aureus (MRSA) as a leading cause of deadly bacterial infections.
The most important currently known virulence factors of C. difficile are Toxin A, Toxin B and the binary toxin CDT. Following endocytosis, acidification of the endosome induces conformational changes of the toxins to induce translocation to the cytoplasm and autocatalytic cleavage and release of the glucosyltransferase domain into the cytosol. These glucosyltransferases catalyse glycosylation and, consequently, the inactivation of Rho-type GTPases. Rho-GTPases control central cellular processes such as the organization of the actin cytoskeleton, epithelial barrier function, motility of the immune cells, polarization of cells, and cell death.
Nevertheless, many questions concerning the multiple cellular functions of the various toxins and their domains remain open. Colonization and infection by C. difficile is strongly dependent on the composition and activities of the gut microbiota. Since faecal microbiota transplantation is a very effective therapeutic approach to treat recurrent C. difficile infections, it is obvious that the microbiota plays a pivotal player in these infections. However, the principles of metabolic crosstalk between the bacterium and host are currently poorly understood. In this context only limited knowledge is available concerning the detailed immune responses of the host. Similarly, progress has been made concerning the gene regulation and proteomic and metabolic networks underlying the adaptation of C. difficile to its hosts. Current studies showed the high strain variability among C. difficile. A wide variety of state-of-the-art methods including genome sequencing, RNAseq-based transcriptomics, quantitative proteomics, metabolomics and bioinformatics, in combination with the genetic tool of gene inactivation, are used to investigate the molecular basis of pathogenicity including sporulation. Still many adaptation strategies and regulatory mechanisms involved remain to be elucidated. In the meantime, hundreds of genomes from multiple C. difficile isolates are available, shedding light on the epidemiology, molecular evolution and biodiversity. Nevertheless, the original reservoir of the bacterium is under discussion.
Overall, this research topic on C. difficile is aimed at assembling current interdisciplinary research for better understanding of the success story of this dangerous bacterial pathogen to create the basis for effective therapy.
The Gram-positive anaerobic bacterium Clostridioides difficile (formerly Clostridium difficile) is becoming a leading cause of detrimental bacterial infections in developed countries. The bacterium is responsible for the majority of antibiotic treatment-associated diarrhoeas. Approximately 453,000 cases of C. difficile infections per year are reported in the USA, with about 29,000 patients dying from it, whereas the prevalence in Germany for unknown reasons is about a fifth of that in the US. Estimated health costs are over $1.5 billion. Overall, the rate of C. difficile infections is growing to replace antibiotic-resistant Staphylococcus aureus (MRSA) as a leading cause of deadly bacterial infections.
The most important currently known virulence factors of C. difficile are Toxin A, Toxin B and the binary toxin CDT. Following endocytosis, acidification of the endosome induces conformational changes of the toxins to induce translocation to the cytoplasm and autocatalytic cleavage and release of the glucosyltransferase domain into the cytosol. These glucosyltransferases catalyse glycosylation and, consequently, the inactivation of Rho-type GTPases. Rho-GTPases control central cellular processes such as the organization of the actin cytoskeleton, epithelial barrier function, motility of the immune cells, polarization of cells, and cell death.
Nevertheless, many questions concerning the multiple cellular functions of the various toxins and their domains remain open. Colonization and infection by C. difficile is strongly dependent on the composition and activities of the gut microbiota. Since faecal microbiota transplantation is a very effective therapeutic approach to treat recurrent C. difficile infections, it is obvious that the microbiota plays a pivotal player in these infections. However, the principles of metabolic crosstalk between the bacterium and host are currently poorly understood. In this context only limited knowledge is available concerning the detailed immune responses of the host. Similarly, progress has been made concerning the gene regulation and proteomic and metabolic networks underlying the adaptation of C. difficile to its hosts. Current studies showed the high strain variability among C. difficile. A wide variety of state-of-the-art methods including genome sequencing, RNAseq-based transcriptomics, quantitative proteomics, metabolomics and bioinformatics, in combination with the genetic tool of gene inactivation, are used to investigate the molecular basis of pathogenicity including sporulation. Still many adaptation strategies and regulatory mechanisms involved remain to be elucidated. In the meantime, hundreds of genomes from multiple C. difficile isolates are available, shedding light on the epidemiology, molecular evolution and biodiversity. Nevertheless, the original reservoir of the bacterium is under discussion.
Overall, this research topic on C. difficile is aimed at assembling current interdisciplinary research for better understanding of the success story of this dangerous bacterial pathogen to create the basis for effective therapy.