Structure-function analysis of large clostridial cytotoxins

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Clostridial glycosylating toxins are important virulence factors causally involved in diseases. They play pivotal roles as pathogenic factors of antibiotics-associated diarrhea and pseudomembranous colitis. In spite of large progress in the analysis of the structure-function-relationship of the toxins, questions of toxin up-take and receptor binding are largely unsolved. To answer these questions, a new short glycosylating toxin (TpeL) from C. perfringens is employed. This toxin has no typical C-terminal receptor binding domain but is still cytotoxic. First studies with a gene trapping method on the basis of haploid cells, resulted in identification of a membrane receptor from the LDL receptor family. The interaction of the toxin with the receptor will be characterized and the role of the receptor in up-take of the toxin studied. It will be analyzed by gene-trapping whether other clostridial glycosylating toxins use the same type of receptors. The identification of membrane receptors is crucial for understanding the mode of action of the toxins and for the development of new therapeutic strategies.