title: Expression of the large clostridial toxins is controlled by conserved regulatory mechanisms.
abstract: The clostridia cause many human and animal diseases, resulting in significant morbidity and mortality. Host damage results from the action of potent exotoxins, an important group of which is the large clostridial toxins (LCTs) produced by Clostridium difficile, Clostridium sordellii, Clostridium perfringens and Clostridium novyi. Knowledge of the structure and function of these toxins has been attained, however, apart from C. difficile, the regulatory pathways that control LCT production remain largely unknown. Here we show that LCT production in C. sordellii and C. perfringens is temporally regulated and repressed by glucose in a similar manner to C. difficile. Furthermore, we show that the TpeL-encoding gene of C. perfringens is located in an uncharacterized Pathogenicity Locus (PaLoc), along with accessory genes predicted to encode a bacteriophage holin-type protein and a TcdR-family alternative sigma factor, TpeR. Inactivation of tpeR demonstrated that TpeR is critical for C. perfringens TpeL production, in a similar manner to C. difficile TcdR and C. sordellii TcsR, but cross-complementation showed that TpeR is not functionally interchangeable with TcdR or TcsR. Although conserved mechanisms are employed by the clostridia to control LCT production there are important functional differences that distinguish members of the TcdR-family of clostridial alternative sigma factors.
authors.affiliation: Department of Microbiology, Monash University, Clayton 3800, VIC, Australia.
authors.forename: Glen P
authors.initials: GP
authors.lastname: Carter
authors.affiliation: Department of Microbiology, Monash University, Clayton 3800, VIC, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Larcombe
authors.affiliation: Department of Microbiology, Monash University, Clayton 3800, VIC, Australia.
authors.forename: Lucy
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Microbiology, Monash University, Clayton 3800, VIC, Australia.
authors.forename: Darshani
authors.initials: D
authors.lastname: Jayawardena
authors.affiliation: Department of Microbiology, Monash University, Clayton 3800, VIC, Australia.
authors.forename: Milena M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, IA 50011-1250, USA.
authors.forename: J Glenn
authors.initials: JG
authors.lastname: Songer
authors.affiliation: Department of Microbiology, Monash University, Clayton 3800, VIC, Australia. Electronic address: dena.lyras@monash.edu.
authors.forename: Dena
authors.initials: D
authors.lastname: Lyras
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics* / Q000378:metabolism*; D003016:Clostridium perfringens / Q000235:genetics* / Q000378:metabolism; D047989:Paraclostridium sordellii / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D015964:Gene Expression Regulation, Bacterial; D023061:Gene Order; D005816:Genetic Complementation Test; D005947:Glucose / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005947:Glucose
keywords: Clostridium difficile; Clostridium disease; Clostridium perfringens; Clostridium sordellii; Large clostridial toxin; Toxin regulation