Typhoid fever is one of the most successful and devastating infectious diseases in human history and remains a serious real-world problem that kills 0.2 million and sickens 21 million people every year. The etiological agent of typhoid fever is the gram-negative bacterium Salmonella enterica serovar Typhi (S. Typhi), which is adapted solely to humans. S. Typhi?s persistent-carriage infection state, exemplified by ?Typhoid Mary,? is critical for person-to-person transmission and the continued maintenance of the bacterium within humans. If we are to effectively contain and eradicate typhoid fever, we need to implement strategies inhibiting S. Typhi?s transition to the persistent infection state. First, however, we must understand how S. Typhi facilitates transition from acute to a persistent/carriage infection state. In a humanized mouse model that serves as a S. Typhi?s persistent infection model, typhoid toxin, a distinct A2B5 toxin or exotoxin produced by intracellular S. Typhi, has been identified as a critical bacterial determinant facilitating the transition of S. Typhi infection to the persistent-carriage infection state. In this R01, we propose a series of experiments to better understand the typhoid toxin-mediated host cell interactive mechanism promoting S. Typhi?s persistent infection. The proposed research may provide critical information for the development of efficacious intervention strategies to better control S. Typhi?s transmission and outbreaks.
Typhoid fever caused by the human-specific pathogen Salmonella enterica serovar Typhi (S. Typhi) is a major global health threat with continuing outbreaks occurring in Southeast Asia and sub-Saharan Africa. Despite appropriate antibiotic treatment and vaccination, typhoid fever results in an estimated 200,000 annual death, mostly among children in low- and middle-income countries. Of concern is the global spread of multidrug- resistant (MDR) and extensively drug-resistant (XDR) strains of S. Typhi. New approaches to prevent and treat MDR and XDR typhoid are urgently needed.