The role of Salmonella Typhi virulence factors in systemic dissemination

PROJECT SUMMARY Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of the systemic illness known as typhoid fever that affects 21 million people each year resulting in an estimated 200,000 deaths. Unlike other Salmonella serovars, S. Typhi is restricted to the human host where it causes a chronic systemic infection characterized by fever and flu-like symptoms. Due to the strict host-specificity of the bacteria, the mouse models available to study typhoid fever are limited to costly humanized mice or the use of the related bacterium Salmonella enterica serovar Typhimurium (S. Typhimurium). While S. Typhimurium and S. Typhi share 89% of their genomes, both serovars contain unique genes with over 600 S. Typhi specific genes, highlighting one of the limitations of using S. Typhimurium to model typhoid fever. Furthermore, in the humanized mouse model, mice are only susceptible to S. Typhi infection through parenteral routes (intraperitoneal or intravenous). For these reasons there is limited knowledge on how S. Typhi uses its virulence factors to invade the gastrointestinal tract and disseminate to systemic sites. Our preliminary results characterize a novel mouse model of typhoid fever in which mice are permissive to S. Typhi infection through a more natural, oral route. This important advancement allows research into the mechanisms of S. Typhi-specific invasion and dissemination from the gastrointestinal tract to be performed. We propose that S. Typhi uses its invasion associated type III secretion system-1 (T3SS-1) and/or flagella to invade the gastrointestinal epithelium and then evades host immune detection via the virulence polysaccharide capsule, Vi. To test this hypothesis, we will combine techniques such as bacterial genetics, antibody mediated neutralization of select cell types, and flow cytometry to assess the host immune response. The proposed research will generate robust and informative information on the mechanism of S. Typhi invasion that can help direct future research on typhoid fever treatment and vaccine development.