title: Pore-forming activity of alpha-toxin is essential for clostridium septicum-mediated myonecrosis.
abstract: Clostridium septicum alpha-toxin is a beta-barrel pore-forming cytolysin that is functionally similar to aerolysin. Residues important in receptor binding, oligomerization, and pore formation have been identified; however, little is known about the activity of the toxin in an infection, although it is essential for disease. We have now shown that deletion of a small portion of the transmembrane domain, so that the toxin is no longer able to form pores, completely abrogates its ability to contribute to disease, as does replacement of the sole cysteine residue with leucine. However, although previous biochemical and cytotoxicity assays clearly indicated that mutations in residues important in oligomerization, binding, and prepore conversion greatly reduced activity or rendered the toxin inactive, once the mutated toxins were overexpressed by the natural host in the context of an infection it was found they were able to cause disease in a mouse model of myonecrosis. These results highlight the importance of testing the activity of virulence determinants in the normal host background and in an infectious disease context and provide unequivocal evidence that it is the ability of alpha-toxin to form a pore that confers its toxicity in vivo.
authors.affiliation: Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Kennedy
authors.forename: Dena
authors.initials: D
authors.lastname: Lyras
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Cordner
authors.forename: Jody
authors.initials: J
authors.lastname: Melton-Witt
authors.forename: John J
authors.initials: JJ
authors.lastname: Emmins
authors.forename: Rodney K
authors.initials: RK
authors.lastname: Tweten
authors.forename: Julian I
authors.initials: JI
authors.lastname: Rood
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D003015:Clostridium Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D052557:Clostridium septicum / Q000472:pathogenicity*; D051379:Mice; D018482:Muscle, Skeletal / Q000382:microbiology* / Q000473:pathology*; D009336:Necrosis; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D052899:Pore Forming Cytotoxic Proteins; C064270:hemolytic toxin, Clostridium septicum