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

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Gibani, Malick M. and Jones, Elizabeth and Barton, Amber and Jin, Celina and Meek, Juliette and Camara, Susana and Galal, Ushma and Heinz, Eva and Rosenberg-Hasson, Yael and Obermoser, Gerlinde and Jones, Claire and Campbell, Danielle and Black, Charlotte and Thomaides-Brears, Helena and Darlow, Christopher and Dold, Christina and Silva-Reyes, Laura and Blackwell, Luke and Lara-Tejero, Maria and Jiao, Xuyao and Stack, Gabrielle and Blohmke, Christoph J. and Hill, Jennifer and Angus, Brian and Dougan, Gordon and Galán, Jorge and Pollard, Andrew J. (2019) Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model. Nature Medicine, 25 (7). pp. 1082-1088. ISSN 1078-8956 (https://doi.org/10.1038/s41591-019-0505-4)

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Abstract

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.

ORCID iDs

Gibani, Malick M., Jones, Elizabeth, Barton, Amber, Jin, Celina, Meek, Juliette, Camara, Susana, Galal, Ushma, Heinz, Eva ORCID logoORCID: https://orcid.org/0000-0003-4413-3756, Rosenberg-Hasson, Yael, Obermoser, Gerlinde, Jones, Claire, Campbell, Danielle, Black, Charlotte, Thomaides-Brears, Helena, Darlow, Christopher, Dold, Christina, Silva-Reyes, Laura, Blackwell, Luke, Lara-Tejero, Maria, Jiao, Xuyao, Stack, Gabrielle, Blohmke, Christoph J., Hill, Jennifer, Angus, Brian, Dougan, Gordon, Galán, Jorge and Pollard, Andrew J.;
CORE (COnnecting REpositories)