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J Exp Med. 2016 May 30;213(6):1061-77. doi: 10.1084/jem.20151025. Epub 2016 May 23.

Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.

Author information

1
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK christoph.blohmke@paediatrics.ox.ac.uk.
2
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK.
3
Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43210.
4
Nuffield Department of Medicine, University of Oxford, OX1 2JD, England, UK.
5
Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
6
Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
7
Nuffield Department of Primary Care Health Sciences, University of Oxford, OX1 2JD, England, UK.
8
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201.
9
Emergent Product Development UK, Emergent BioSolutions, Wokingham RG41 5TU, England, UK.
10
EMBL Australia Group, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia School of Medicine, Flinders University, Bedford Park, SA 5042, Australia.

Abstract

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.

PMID:
27217537
PMCID:
PMC4886356
DOI:
10.1084/jem.20151025
[Indexed for MEDLINE]
Free PMC Article

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