Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.
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Date
2016-05-30Author
Blohmke, CJ
Darton, TC
Jones, C
Suarez, NM
Waddington, CS
Angus, B
Zhou, L
Hill, J
Clare, S
Kane, L
Mukhopadhyay, S
Schreiber, F
Duque-Correa, MA
Wright, JC
Roumeliotis, TI
Yu, L
Choudhary, JS
Mejias, A
Ramilo, O
Shanyinde, M
Sztein, MB
Kingsley, RA
Lockhart, S
Levine, MM
Lynn, DJ
Dougan, G
Pollard, AJ
Type
Journal Article
Metadata
Show full item recordAbstract
Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.
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Subject
Humans
Salmonella typhi
Typhoid Fever
Tryptophan
Interferon Type I
Adult
Middle Aged
Female
Male
Interferon-gamma
Immunomodulation
Research team
Functional Proteomics Group
Language
eng
Date accepted
2016-04-08
License start date
2016-05-23
Citation
The Journal of experimental medicine, 2016, 213 (6), pp. 1061 - 1077
Publisher
ROCKEFELLER UNIV PRESS