期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 6, 页码 1061-1077出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151025
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资金
- Emergent BioSolutions
- National Institute for Health Research Clinical Research Network
- Wellcome Trust [092661]
- Newton Fund
- Medical Research Council [MR/M02637X/1]
- FP7 program of the European Union
- European Molecular Biology Organization
- National Institute for Health Research Oxford Biomedical Research Centre
- Jenner Institute
- Oxford Martin School
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01 AI-036525, U-19 AI-082655, U19-AI109776]
- European Molecular Biology Laboratory Australia
- [U-19 AI089987]
- [U-19 AI057234]
- [U01 AI82210]
- MRC [MR/M02637X/1] Funding Source: UKRI
- Medical Research Council [MR/M02637X/1] Funding Source: researchfish
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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