title: Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.
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.
authors.affiliation: 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.
authors.forename: Christoph J
authors.identifier: 0000-0002-1453-9651
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK.
authors.forename: Thomas C
authors.identifier: 0000-0003-2209-9956
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43210.
authors.forename: Nicolas M
authors.identifier: 0000-0001-8429-8374
authors.initials: NM
authors.lastname: Suarez
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Nuffield Department of Medicine, University of Oxford, OX1 2JD, England, UK.
authors.forename: Brian
authors.identifier: 0000-0003-3598-7784
authors.initials: B
authors.lastname: Angus
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK.
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hill
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Leanne
authors.identifier: 0000-0002-2241-8120
authors.initials: L
authors.lastname: Kane
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Schreiber
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Maria A
authors.identifier: 0000-0002-0567-0412
authors.initials: MA
authors.lastname: Duque-Correa
authors.affiliation: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: James C
authors.identifier: 0000-0001-6950-4328
authors.initials: JC
authors.lastname: Wright
authors.affiliation: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Theodoros I
authors.initials: TI
authors.lastname: Roumeliotis
authors.affiliation: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.affiliation: Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Jyoti S
authors.identifier: 0000-0003-0881-5477
authors.initials: JS
authors.lastname: Choudhary
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43210.
authors.forename: Asuncion
authors.identifier: 0000-0002-5983-8006
authors.initials: A
authors.lastname: Mejias
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43210.
authors.forename: Octavio
authors.initials: O
authors.lastname: Ramilo
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, OX1 2JD, England, UK.
authors.forename: Milensu
authors.identifier: 0000-0003-4842-9247
authors.initials: M
authors.lastname: Shanyinde
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kingsley
authors.affiliation: Emergent Product Development UK, Emergent BioSolutions, Wokingham RG41 5TU, England, UK.
authors.forename: Stephen
authors.identifier: 0000-0002-0805-2193
authors.initials: S
authors.lastname: Lockhart
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: 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.
authors.forename: David J
authors.identifier: 0000-0003-4664-1404
authors.initials: DJ
authors.lastname: Lynn
authors.affiliation: Microbial Pathogenesis Group, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, England, UK.
authors.forename: Gordon
authors.identifier: 0000-0003-0022-965X
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford OX3 7LE, England, UK.
authors.forename: Andrew J
authors.identifier: 0000-0001-7361-719X
authors.initials: AJ
authors.lastname: Pollard
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D056747:Immunomodulation; D007370:Interferon Type I / Q000097:blood / Q000276:immunology*; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012485:Salmonella typhi / Q000276:immunology* / Q000378:metabolism; D014364:Tryptophan / Q000096:biosynthesis / Q000276:immunology*; D014435:Typhoid Fever / Q000097:blood / Q000276:immunology* / Q000473:pathology
chemical_list: D007370:Interferon Type I; D007371:Interferon-gamma; D014364:Tryptophan