Studies on the toxic action of cytolethal toxin from Clostridium septicum.

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The activity of Clostridium septicum alpha-toxin was determined in erythrocytes of various animals. It was shown that hemolytic activities of alpha-toxin associated with specific erythrocyte membrane proteins that were subsets of GPI-anchored proteins in various animal species. I examined molecular mechanisms of oligomer formation of alpha-toxin on mammalian cells using mouse connective tissue cell line, L-929. After the protoxin binds to GPI-anchored proteins in non-raft for activation by cell surface protease, activated toxin moves to lipid raft and oligomerizes leading to pore-formation. It was also shown that cholesterol played a significant role in alpha-toxin oligomerization and cytotoxicity. Alpha-actin was identified as a new toxin-binding protein, which provided some information to elucidate peculiar symptoms such as malignant edema involving C.septicum infection. Malignant edema is a disease condition of muscle tissues and the ultimate cause of the death is heart failure. I proved that alpha-toxin specifically interact with alpha-actin after binding to cell membrane and pore formation. It was observed that the heart beat has immediately stopped in primary mouse cardiac cells and rat perfused heart without necrosis after inoculation of alpha-toxin. These results indicate that alpha-toxin can induce cardiac arrest with the other mechanism than cell necrosis. In future, I will estimate relevances between heart failure and binding of alpha-toxin to actin in molecular and cellular level.