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Nat Med. 2019 Jul;25(7):1082-1088. doi: 10.1038/s41591-019-0505-4. Epub 2019 Jul 3.

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

Author information

1
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK. malick.gibani@paediatrics.ox.ac.uk.
2
Department of Medicine, Imperial College London, London, UK. malick.gibani@paediatrics.ox.ac.uk.
3
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
4
Nuffield Department of Primary Care Health Sciences, Clinical Trials Unit, University of Oxford, Oxford, UK.
5
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
6
Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
7
Human Immune Monitoring Center, Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
8
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
9
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
10
Department of Medicine, University of Cambridge, Hinxton, UK.

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.

PMID:
31270506
DOI:
10.1038/s41591-019-0505-4

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