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

Christoph J. Blohmke, Thomas C. Darton, Claire Jones, Nicolas M. Suarez, Claire S. Waddington, Brian Angus, Liqing Zhou, Jennifer Hill, Simon Clare, Leanne Kane, Subhankar Mukhopadhyay, Fernanda Schreiber, Maria A. Duque-Correa, James C. Wright, Theodoros I. Roumeliotis, Lu Yu, Jyoti S. Choudhary, Asuncion Mejias, Octavio Ramilo, Milensu ShanyindeMarcelo B. Sztein, Robert A. Kingsley, Stephen Lockhart, Myron M. Levine, David Lynn, Gordon Dougan, Andrew J. Pollard

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1061-1077
Number of pages17
JournalJournal of Experimental Medicine
Volume213
Issue number6
DOIs
Publication statusPublished - 30 May 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this