1. What makes S. Typhi so pathological? – with an emphasis on Typhoid toxin’s contribution.

Typhoid fever remains a serious real-world problem that kills 0.2 million and sickens 21 million people every year. Reflecting its significance, Salmonella Typhi, the cause of typhoid fever, is one of the NIAID category B priority pathogens, is listed as a CDC antibiotic/antimicrobial resistance serious threat, and is on the WHO’s high priority pathogen list. Recent epidemiology studies reveal that multidrug-resistant (MDR) strains of S. Typhi are rapidly spreading. This escalation justifies the need for alternative strategies to combat MDR S. Typhi. An effective alternative strategy would be targeting essential virulence mechanisms of typhoid fever. However, little is known about the pathogenic mechanisms specific to S. Typhi.

One such essential virulence factor specific to S. Typhi is a recently discovered toxin: typhoid toxin. Typhoid toxin has many unique structural and functional features. This toxin consists of three subunits, CdtB (nuclease), PltA (mono ADP ribosyltransferase), and a homopentemer of PltB (receptor binding), resulting in its unique A2B5 stoichiometry. When administered to laboratory animals, typhoid toxin recapitulated many of the characteristic signs and symptoms of typhoid fever including leukopenia and neurological complications. It is expected that typhoid toxin plays a similar role during human infection, which is supported by (1) clinical reports indicating the abundant presence of anti-typhoid toxin antibodies in the sera of people recovering from acute typhoid fever, and (2) our recent studies demonstrating primary human cells and tissues related to typhoid signs express the specific glycan receptor for typhoid toxin. However, we do not have a good understanding of how each subunit of typhoid toxin contributes to its virulence.

To fill this gap in our knowledge, we perform research to determine precise role(s) of typhoid toxin’s subunits in virulence, with an emphasis on roles of PltA and PltB.

2. Despite an extremely narrow host range, what makes S. Typhi so successful? – with an emphasis on Typhoid toxin’s contribution.

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 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 ultimately 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 the acute infection state to the persistent-carriage infection state. Using a humanized mouse model to recreate S. Typhi’s persistent infection, typhoid toxin has been identified as a critical bacterial determinant facilitating the transition of S. Typhi infection to the persistent-carriage infection state. We perform a series of experiments to better understand the typhoid toxin-mediated host cell interactive mechanism promoting S. Typhi’s persistent infection. We predict that this research will offer critical information for the development of efficacious intervention strategies to better control S. Typhi’s transmission and outbreaks.