Grant: Project Grant

Salmonella Typhi is a human-adapted serotype of the common bacterial pathogen Salmonella enterica, and is the cause of the life-threatening disease typhoid fever. Typhoid fever is a major health issue in the developing world, affecting millions of people worldwide each year. Recently, the prevalence of multi-drug antibiotic resistant strains of S. Typhi has expanded sharply, and the available treatment options for this life-threatening disease are dwindling. S. Typhi secretes a potent toxin, typhoid toxin, that enters and damages human cells during infection. Typhoid toxin is an important S. Typhi virulence factor and is a promising target for new interventions to combat typhoid fever, however there is a great deal we do not know about this toxin. Typhoid toxin biology is unusually complex compared to other bacterial toxins; for example, we recently discovered that S. Typhi produces two different versions of typhoid toxin that have different cell targeting mechanisms. This project takes a multi-faceted approach to investigate major outstanding questions concerning typhoid toxin biology. The approaches taken here to investigate typhoid toxin will also shed light on broader aspects of bacterial pathogenesis, such as how pathogens adapt to a human host, and identifying the mechanisms that Salmonella uses for long-term survival within a human cell. The major outcome of this project will be an improved understanding of important aspects of Salmonella Typhi pathogenesis that are relevant to the design and implementation of badly needed new interventions to combat typhoid fever.