Mechanisms by which ICP3 Overcomes Vibrio cholerae Phage Defenses

PROJECT SUMMARY Bacteriophages (phages) are bacteria-specific viruses. Phages play a major role in the life cycle and evolution of Vibrio cholerae, the bacteria that causes cholera. Despite the presence of many V. cholerae-specific phage types in the environment, only three types, ICP1, ICP2 and ICP3, are commonly found at high concentrations in the watery diarrhea shed by cholera patients. Thus, these three phages are special for their ability to survive in the human intestinal tract, where they replicate on and kill V. cholerae. Of these phages, ICP3 is the most virulent in terms of its ability to kill V. cholerae. The emergence of resistance to ICP1, ICP2 and to other phages is frequent in V. cholerae, but, for unknown reasons, resistance to ICP3 is exceedingly rare. This makes ICP3 of great interest for use as a product to treat or prevent cholera. The use of phages for therapy or prevention of bacterial infections is gaining broad interest due to the emergence of multidrug resistance in many bacterial pathogens, including V. cholerae. To gain a better understanding of ICP3's virulence and lack of emergence of host resistance, in this exploratory project we will delete each of the approximately four dozen accessory genes of ICP3 and test their roles in circumventing the phage defense systems of V. cholerae. Addionally, we will identify the cognate host phage defense genes in V. cholerae for each ICP3 accessory gene. The results will shed much light on ICP3's special abilities, and will encourage the development of ICP3 into a product for use in combatting cholera.