Phage Resistance in Emergent Vibrio cholerae and Phage Prophylaxis of Cholera

Bacteriophages (phages) are viruses that specifically kill bacteria but are safe for humans. Phages have been shown to play important roles in the life cycle of many bacterial pathogens, particularly water-borne pathogens that cause gastrointestinal tract infections. For example, the temperate phages, which integrate their DNA into the bacterial genome, often increase the fitness of their host by providing virulence factors such as toxins. Other phages, known as lytic or virulent phages, can play negative roles by infecting and killing their host bacterium, thus reducing the number of pathogen below the threshold needed to cause disease. Vibrio cholerae is a water-borne pathogen that infects the small intestine to cause the severe diarrheal disease cholera. Our published and preliminary data indicate a pervasive negative role for several virulent phages commonly found in cholera-endemic areas around the Bay of Bengal. These virulent phages reduce the virulence, transmission, and dissemination of V. cholerae. Sensitivity to most of these phages, particularly to phage ICP3, has been consistent among clinical isolates collected over the past 20 years, opening up the possibility of using a cocktail of phages for preventing cholera in people at high risk, such as household contacts of cholera index patients. However, in 2022, a new multidrug-, multiphage- resistant strain emerged in Bangladesh that threatens the prevention and treatment of cholera. ICP3 alone retains the ability to kill this newly emerged strain. In this project, we will investigate the potential of ICP3 as a single phage product for preventing cholera. We will determine if there is a mucosal immune response to orally administered ICP3 and whether it is neutralizing. In addition, we will identify and characterize phage resistance mechanisms in emergent strains of V. cholerae. RELEVANCE (See instructions): Cholera is a devastating disease with over one billion people at risk. This project will evaluate a new way of preventing cholera using a bacteriophage, which is a type of virus that specifically kills bacteria but is safe for humans.