1. Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model
- Author
-
Ushma Galal, Jorge E. Galán, Gabrielle Stack, Danielle Campbell, Gordon Dougan, Christopher A Darlow, Jennifer Hill, Amber J Barton, Celina Jin, L Blackwell, Elizabeth Jones, Xuyao Jiao, Charlotte Black, Brian Angus, Yael Rosenberg-Hasson, Christoph J. Blohmke, Maria Lara-Tejero, Claire Jones, Helena Thomaides-Brears, Gerlinde Obermoser, Andrew J. Pollard, Malick M. Gibani, Eva Heinz, L Silva-Reyes, Christina Dold, Juliette Meek, Susana Camara, Gibani, Malick M [0000-0003-1781-0053], Heinz, Eva [0000-0003-4413-3756], Campbell, Danielle [0000-0001-5794-8036], Angus, Brian [0000-0003-3598-7784], Galán, Jorge [0000-0002-6531-0355], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Letter ,Research & Experimental Medicine ,Salmonella typhi ,medicine.disease_cause ,Pathogenesis ,Mice ,0302 clinical medicine ,Clinical trials ,Pathogen ,11 Medical and Health Sciences ,ENTERICA SEROVAR TYPHI ,SALMONELLA-TYPHI ,General Medicine ,Middle Aged ,3. Good health ,Clinical trial design ,Experimental models of disease ,Medicine, Research & Experimental ,030220 oncology & carcinogenesis ,Acute Disease ,Life Sciences & Biomedicine ,Adult ,Biochemistry & Molecular Biology ,Adolescent ,Bacterial Toxins ,Immunology ,Context (language use) ,complex mixtures ,General Biochemistry, Genetics and Molecular Biology ,Typhoid fever ,03 medical and health sciences ,Young Adult ,Double-Blind Method ,PARATYPHI ,medicine ,Animals ,Humans ,Typhoid Fever ,Science & Technology ,business.industry ,Toxin ,Bacteriology ,Cell Biology ,Translational research ,medicine.disease ,bacterial infections and mycoses ,Mice, Inbred C57BL ,Chronic infection ,030104 developmental biology ,Bacteremia ,CELLS ,business ,HUMAN INFECTION MODEL - 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., Typhoid toxin is not essential for the pathogenesis of typhoid fever in healthy humans challenged with Salmonella Typhi.
- Published
- 2019