April 21, 2020  |  

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

Authors: 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

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.

Journal: Nature medicine
DOI: 10.1038/s41591-019-0505-4
Year: 2019

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