Cytopathogenic Action of Clostridium Difficile Toxins

Two toxins from Clostridium difficile, designated toxins A and B, are essential in the pathogenesis of antibiotic-associated colitis in humans. The toxins are high molecular weight proteins which can be separated by ion exchange chromatography of culture supernatants.In all cultured mammalian cells tested, both toxins induce the same characteristic cytopathogenic effect which resembles that induced by cytochalasin B. Toxin B, however, has a much higher potency as a cytotoxin than toxin A- Toxin A causes fluid accumulation in rabbit ileal loops whereas toxin B is devoid of enterotoxic activity. Both toxins agglutinate rabbit erythrocytes. The mode of cellular intoxication with toxin A is poorly understood. For toxin B some parts of the intoxication process have been elucidated. After binding to the cell surface toxin B is internalized into the cell by endocytosis. It is suggested that toxin B is processed in the lysosomes, and then transferred to the cytosol, probably via membrane channels induced at the low intralysosomal pH. Toxin B has no primary effect on the cell membrane, the DNA-, RNA-, or protein synthesis, or on the energy metabolism. The intracellular intoxicative steps require energy, but proceed unaltered in the absence of DNA-, RNA-, or protein synthesis. The microfilament system is proposed as main target for toxin B. Possible relationships between toxin A and B and other clostridial toxins are discussed.