Clostridium difficile toxins A and B: exploring the possible mechanism of action
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Clostridium difficile is a common cause of antibiotic-associated diarrhea and occasionally causes the life-threatening disease pseudomembranous colitis. The pathogenicity of the organism has been attributed to the production of two large exotoxins, toxin A (308,000 daltons) and toxin B (269,000 daltons). Toxin A is a powerful enterotoxin and is generally thought to play the more important role in the pathology of the disease. Toxin B may exert its effect after the initial tissue damage by toxin A. Both toxins cause rounding of mammalian culture cells by disrupting the cytoskeletal system. The similar biological activities and high percentage of sequence homology between the two toxins suggest that they have a similar mechanism of action. I found that purified preparations of both toxins cleave skeletal muscle actin at a single site, producing a 38,000 dalton actin fragment, and that the toxins are capable of autodigestion. The proteolytic activity may be involved in the mechanism of action of the toxins. I also analyzed an aberrant strain of C. difficile which reportedly lacked the gene for toxin B. Such a strain would be very useful for the study of the mechanism of toxin A. I concluded however, that the strain contained the genes for both toxin A and toxin B. The toxin genes and resulting proteins appear, however, to be slightly different from those of other strains.
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