Grant: Doctoral Research Award: Canada Graduate Scholarships

In 2017, the global burden of typhoid fever was estimated at 10.9 million cases. The causative agent of typhoid fever, Salmonella Typhi, uses a unique virulence factor to cause disease in humans: the typhoid toxin (TT). Several studies have shown that TT damages human cells and is directly responsible for some of the symptoms of typhoid fever. Thus, TT is thought to play a key role in how S. Typhi persists as a human pathogen. As such, TT offers a promising target to treat cases of typhoid fever. However, this unusual toxin assembles as two different variants which bind different human cells and cause different symptoms. Thus, Salmonella experiences a dilemma in balancing the expression of its two forms of TT. How Salmonella determines which TT to produce is poorly understood, but is thought to be a critical aspect of its biology. Recent data show that Salmonella appear to sense pyrimidine or purine starvation to produce one toxin over another. We hypothesize that several genes in Salmonella are mediating this unknown mechanism. To understand how Salmonella balances TT production, this project will use large-scale screening approaches to identify which genes change expression during pyrimidine or purine starvation. These genes will be targeted for further experiments by deleting them in Salmonella Typhi and quantifying the expression of TT. Understanding how Salmonella balances TT production will be important in designing treatments which target TT. Ultimately, this project will advance efforts to combat the global burden of typhoid fever.