Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model.

Gibani MM., Jones E., Barton A., Jin C., Meek J., Camara S., Galal U., Heinz E., Rosenberg-Hasson Y., Obermoser G., Jones C., Campbell D., Black C., Thomaides-Brears H., Darlow C., Dold C., Silva-Reyes L., Blackwell L., Lara-Tejero M., Jiao X., Stack G., Blohmke CJ., Hill J., Angus B., Dougan G., Galán J., Pollard AJ.

Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually1. The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction2-6. However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model7. Forty healthy volunteers were randomized (1:1) to oral challenge with 104 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9-97.0) versus 30.3(3.6-49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage.

DOI

10.1038/s41591-019-0505-4

Type

Journal article

Journal

Nat Med

Publication Date

07/2019

Volume

25

Pages

1082 - 1088

Keywords

Acute Disease, Adolescent, Adult, Animals, Bacterial Toxins, Double-Blind Method, Humans, Mice, Mice, Inbred C57BL, Middle Aged, Salmonella typhi, Typhoid Fever, Young Adult

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