Investigating the dynamics of Salmonella Typhi and bacteriophages in the environment and the human gut

Salmonella Typhi, the causative agent of typhoid fever, is a neglected tropical disease that spreads through contaminated food and water. Recent environmental surveillance studies from Bangladesh and Nepal have found that prevalence of Typhi-specific bacteriophages in wastewater correlated with the burden of typhoid fever in the community. Preliminary studies from our group have uncovered that different genotypes of Salmonella Typhi have differing phage susceptibility. Three of the most commonly circulating genotypes in Bangladesh (4.3.1.1, 3.3.2 and 4.3.1.3. Bdq) exhibit high phage resistance, suggesting a link between phage resistance and the fitness and spread of Salmonella Typhi. Genomic analysis identified that 4.3.1.3. Bdq possesses the BREX anti-phage defense system, but no known phage defense systems could be identified in genotypes 4.3.1.1 and 3.3.2. In the proposed study, we want to use genetic, molecular, and biochemical methods to dissect the interaction between bacteriophages and different strains of Salmonella Typhi to a) identify the molecular factors that dictate Salmonella Typhi and phage interactions, and b) investigate how these factors change over time in both the bacteria and phages. We also propose a longitudinal observational study to identify prevalence of Typhi-specific phages in the human gut and their correlation with typhoid fever. Taken together, this study will shed light on the role phages play in dictating the spread and evolution of an important, but often, neglected infectious disease.