Gibani, Malick M; Jones, Elizabeth; Barton, Amber; Jin, Celina; Meek, Juliette; Camara, Susana; Galal, Ushma; Heinz, Eva; Rosenberg-Hasson, Yael; Obermoser, Gerlinde; +17 more... 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; 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 DOI: 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.
Item Type | Article |
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Faculty and Department | Faculty of Infectious and Tropical Diseases > Dept of Clinical Research |
PubMed ID | 31270506 |
Elements ID | 140344 |
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