Investigating Host Responses to Salmonella Typhi in Acute Typhoid Fever

Salmonella Typhi causes acute typhoid fever through virulence factors, which includes the typhoid toxin that causes DNA damage in human cells. In 2019, colleagues at the University of Oxford studied the typhoid toxin during typhoid fever by challenging human participants with wild-type (WT) or toxin-negative (TN) strains of S. Typhi. In participants’ bloodstream, TN S. Typhi persisted for up to 96 hours while WT S. Typhi were eliminated from the blood by 48 hours. This suggests DNA damage caused by typhoid toxin alerted immune defences in humans that countered bloodstream infection. To resolve differences in the host response to bacteraemia by WT and TN S. Typhi, proteomics identified protein signatures secreted in the plasma of bacteraemic participants with acute typhoid fever (‘secretome-WT’). Relative to uninfected participants, the plasma of those infected with WT S. Typhi contained significantly regulated proteins by typhoid toxin. Of those proteins, only Apolipoprotein C3 (APOC3) and lysozyme (LYZ) were differentially regulated between WT- and TN-infected indicating a role in mediating clearance of S. Typhi. In vitro experiments show DNA damage induced by purified recombinant typhoid toxin or infection by toxigenic Salmonella elicited DNA damage responses and cell-cycle arrest, which was coincident with increased expression and secretion of APOC3 and LYZ. Importantly, further in vitro experiments established that LYZ kills Salmonella in a dose dependent manner, which could explain how WT S. Typhi are eliminated from blood quicker than TN S. Typhi. Ongoing experiments are addressing the putative antimicrobial role of APOC3. This project sheds light on host innate immune responses activated by bacterial-induced DNA damage and highlights that virulence factors can be viewed as double-edged swords, which promote infection but may also alert host defence.