Analysis of toxin secretion in the large clostridial toxin (LCT) producing clostridia

The LCT-producing clostridia are an important group of pathogens that cause severe disease in both humans and animals. In most cases the diseases caused by these organisms are at least partly mediated by the production of potent exotoxins known as the large clostridial toxins (LCTs), which are mono-glycosyltransferases that irreversibly inactivate members of the Rho family of small GTPases. These toxins are structurally related and reside within a genomic region known as the Pathogenicity Locus (PaLoc) that also encodes several accessory proteins thought to be involved in the control of toxin production and secretion. None of the LCTs have any recognisable signal peptides or export sequences, suggesting that they are secreted by a novel mechanism, potentially involving holin-like proteins. The aim of this project is to further define the mechanism by which the LCTs are secreted from the cell. This will be achieved through the construction of isogenic mutants in the LCT-producing clostridia and subsequent phenotypic testing, as well as through the purification and testing of proteins hypothesised to be involved in the export process.