Development of therapeutic blocking agents and improved vaccines against cholera

Currently available vaccines against cholera have insufficient efficacy, especially for children in endemic areas. The severity of cholera diarrhea differs dramatically between individuals but the underlying reason is not known.

The purpose of my research is to develop therapeutic blocking reagents and improved vaccines against enterotoxigenic bacteria.We predict that such improved treatments can spring from a deeper understanding of how the causative agent Cholera toxin (CT) binds to ligands expressed by the intestinal cells that initiate the diarrhea.

Our recently published data have changed the dogma of how CT intoxicates intestinal cells and also identified three novel possible mechanisms for binding site usage.

In this 3-year project we will use binding-site specific CT mutants and human enteroids to establish how CT-binding sites are utilized for intoxication of non-transformed human small intestinal cells.Detoxified CT variants are promising oral adjuvants but their mode of action remains undefined.

Hence, we will also exploit the mutants to determine the binding site and intracellular pathways needed for human immune cell activation and adjuvant capacity by detoxified CT.We anticipate that our results, in addition to aid the development of improved vaccine, also will facilitate the generation of binding-site-specific antidotes to be given to unvaccinated individuals following a natural disaster or in refugee camps with poor water and sanitary conditions.