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

Christoph Blohmke, Thomas Darton, Claire Jones, Nicolas Suarez, Claire Waddington, Brian Angus, Liqing Zhou, Jennifer Hill, Simon Clare, Leanne Kane, Subhankar Mukhopadhyay, Fernanda Schreiber, Maria Duque-Correa, James Wright, Theodoros Roumeliotis, Lu Yu, Juoti Choudhary, Asuncion Mejias, Octavio Ramilo, Milensu ShanyindeMarcelo Sztein, Robert Kingsley, Stephen Lockhart, Myron Levine, David Lynn

    Research output: Contribution to journalArticlepeer-review

    20 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 - 2016

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