Salmonella Typhi: Enhancement of Endemic Potential through its Unique Virulence Factors

PROJECT SUMMARY/ABSTRACTTyphoid fever is one of the most successful and devastating infectious diseases in human history and remainsa serious real-world problem that kills 0.2 million and sickens 21 million people every year. The etiological agentof typhoid fever is the gram-negative bacterium Salmonella enterica serovar Typhi (S. Typhi), which is adaptedsolely to humans. S. Typhi?s persistent-carriage infection state, exemplified by ?Typhoid Mary,? is critical forperson-to-person transmission and the continued maintenance of the bacterium within humans. If we are toeffectively contain and eradicate typhoid fever, we need to implement strategies inhibiting S. Typhi?s transitionto the persistent infection state. First, however, we must understand how S. Typhi facilitates transition from acuteto a persistent/carriage infection state. In a humanized mouse model that serves as a S. Typhi?s persistentinfection model, typhoid toxin, a distinct A2B5 toxin or exotoxin produced by intracellular S. Typhi, has beenidentified as a critical bacterial determinant facilitating the transition of S. Typhi infection to the persistent-carriageinfection state. In this R01, we propose a series of experiments to better understand the typhoid toxin-mediatedhost cell interactive mechanism promoting S. Typhi?s persistent infection. The proposed research may providecritical information for the development of efficacious intervention strategies to better control S. Typhi?stransmission and outbreaks.