Bacterial Enterotoxins as Immunomodulators andVaccine Adjuvants
Johan Mattsson and Nils Lycke
from: Bacterial Toxins: Genetics, Cellular Biology and Practical Applications (Edited by: Thomas Proft). Caister Academic Press, U.K. (2013)
The bacterial enterotoxins , cholera toxin (CT) and the closely related E.coli heat-labile toxin (LT) have been found to be the most potent mucosal immunoenhancers (adjuvants) we know of today. Hence, much research is focused on understanding the mechanism behind their potent augmenting function following mucosal immunizations and oral immunizations, in particular. These holotoxins consist of an AB5 structure, where the A1-subunit hosts ADP-ribosylating activity and the B-subunit is the receptor binding element, which exists as a pentamer and specifically binds to GM1 ganglioside on the membrane of most mammalian cells. The A1 and B-subunit pentamer are attached through the linker A2. Because of severe toxicity of the holotoxins following either oral or nasal administration clinical use of the holotoxins is precluded. Therefore, attempts to mutate the A-subunit so as to reduce enzymatic activity with retained augmenting effect have been successful. However, we have developed the CTA1-DD molecule which has retained the full enzymatic activity of CT, but without the toxic side effects of the holotoxin. In the present review we describe the mechanism of action for ADP-ribosylating holotoxins and we discuss the mechanistic benefits of mutant holotoxins or the unique CTA1-DD adjuvant for future prospects of developing effective mucosal vaccines in general and oral vaccines, in particular read more ...