Cholera toxin and related enterotoxins: a cell biological and immunological perspective

Cholera toxin (Ctx) from Vibrio cholerae and the closely related Escherichia coli heat-labile enterotoxin (Etx) are the primary virulence factors responsible for causing cholera and traveller's diarrhea, respectively. Studies on the mode of action of these toxins on gut epithelial cells have revealed important insights into the mechanisms of toxin uptake and trafficking in eukaryotic cells. However, of perhaps even greater fascination have been the discoveries that Ctx and Etx exhibit remarkable immunological properties. When either of these toxins is administered via mucosal routes, it triggers a potent mucosal and systemic anti-toxin immune response. By contrast, local or systemic immunization with other soluble protein antigens usually stimulates only a meagre immune response, or results in a state of immunological tolerance. Even more striking are the findings that when Ctx or Etx are mixed with heterologous antigens, they function as adjuvants, leading to stimulation of mucosal responses to the admixed antigen, and the abrogation of oral tolerance. In addition, recent observations have shown that the receptor-binding component of these toxins can down-regulate inflammatory diseases associated with the induction of autoimmune disorders such as rheumatoid arthritis, diabetes, and multiple sclerosis. While the underlying mechanisms responsible for these remarkable properties have yet to be resolved, it is clear that the toxins' ability to bind to cell surface receptors plays an important role in their potent immunogenicity, adjuvanticity, and immunotherapeutic properties. This review provides an overview of the latest developments within the Ctx/Etx field, with a special emphasis on the cell entry mechanisms and immunomodulatory action of Ctx/Etx and their component subunits.