title: Integration of metabolism and virulence in Clostridium difficile.
abstract: Synthesis of the major toxin proteins of the diarrheal pathogen, Clostridium difficile, is dependent on the activity of TcdR, an initiation (sigma) factor of RNA polymerase. The synthesis of TcdR and the activation of toxin gene expression are responsive to multiple components in the bacterium's nutritional environment, such as the presence of certain sugars, amino acids, and fatty acids. This review summarizes current knowledge about the mechanisms responsible for repression of toxin synthesis when glucose or branched-chain amino acids or proline are in excess and the pathways that lead to synthesis of butyrate, an activator of toxin synthesis. The regulatory proteins implicated in these mechanisms also play key roles in modulating bacterial metabolic pathways, suggesting that C. difficile pathogenesis is intimately connected to the bacterium's metabolic state.
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Electronic address: laurent.bouillaut@tufts.edu.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bouillaut
authors.affiliation: Laboratoire Pathogenèse des Bactéries Anaérobies, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, France. Electronic address: tdubois@pasteur.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dubois
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Electronic address: linc.sonenshein@tufts.edu.
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Sonenshein
authors.affiliation: Laboratoire Pathogenèse des Bactéries Anaérobies, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, France. Electronic address: bdupuy@pasteur.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dupuy
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D001427:Bacterial Toxins / Q000096:biosynthesis*; D002087:Butyrates / Q000378:metabolism; D016360:Clostridioides difficile / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D012808:Sigma Factor / Q000378:metabolism; D014774:Virulence
chemical_list: D000596:Amino Acids; D001427:Bacterial Toxins; D002087:Butyrates; D005227:Fatty Acids; D012808:Sigma Factor; D005947:Glucose
keywords: Clostridium difficile; Metabolic regulation; Redox state; Stickland metabolism; Toxinogenesis