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

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Gibani, MM ORCID: 0000-0003-1781-0053, Jones, E, Barton, A, Jin, C, Meek, J, Camara, S, Galal, U, Heinz, E ORCID: 0000-0003-4413-3756, Rosenberg-Hasson, Y, Obermoser, G et al (show 17 more authors) , Jones, C, Campbell, D ORCID: 0000-0001-5794-8036, Black, C, Thomaides-Brears, H, Darlow, C ORCID: 0000-0002-5400-3413, Dold, C, Silva-Reyes, L, Blackwell, L, Lara-Tejero, M, Jiao, X, Stack, G, Blohmke, CJ, Hill, J, Angus, B ORCID: 0000-0003-3598-7784, Dougan, G, Galán, J ORCID: 0000-0002-6531-0355 and Pollard, AJ (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, 1546-170X

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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 restriction^2–6. 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
Uncontrolled Keywords:	Animals, Mice, Inbred C57BL, Humans, Mice, Salmonella typhi, Typhoid Fever, Acute Disease, Bacterial Toxins, Double-Blind Method, Adolescent, Adult, Middle Aged, Young Adult
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	08 Sep 2021 09:34
Last Modified:	01 Mar 2026 01:53
DOI:	10.1038/s41591-019-0505-4
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3136358
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