Grant: Operating Grant

The emergence of new and drug-resistant variants of microbial agents of disease (known as pathogens) represents a challenge to human health. The objective of the proposed research is to understand how these disease-causing entities sense their host environment to coordinate the productions of poisonous substances (toxins). Our goal is to identify novel drug targets for alternative therapies. We are studying Vibrio cholerae, the bacterium that causes cholera - an infection of the small intestine that causes severe watery diarrhea, dehydration, and over 120,000 deaths every year. The delivery of toxins is a common mechanism bacteria use to cause disease. We have discovered a novel mechanism by which V. cholerae delivers toxins to kill other bacteria as well as cells of the human immune system. The bacterium assembles a molecular syringe on its surface that injects toxins into bacteria and mammalian cells it comes in contact with. We hypothesize that V. cholerae uses this mechanism to cause infections. To accomplish this killing, V. cholerae bacteria must be protected from their own toxins, and in confirmation of this prediction, we have identified "immunity genes" that render V. cholerae resistant to toxins delivered by this molecular syringe. This project is designed to expand our knowledge on how this delivery mechanism contributes to microbial infections. We plan to do this by studying when the toxins are produced, where the toxins go, and what the toxins do in the infected host. We anticipate that our findings will help us identify weaknesses that can be exploited therapeutically for the large number of pathogens whose genomes contain the information for this virulence mechanism. The immunity genes are intriguing therapeutic targets for a number of reasons. Perhaps the most important reason is that if we can temporarily suppress the immunity genes, the bacteria will use their molecular syringes to kill each other and this could be used to help clear infections.