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: 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 Shanyinde, Marcelo B Sztein, Robert A Kingsley, Stephen Lockhart, Myron M Levine, David J Lynn, Gordon Dougan, Andrew J Pollard
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 213 Issue 6 Pg. 1061-77 (05 30 2016) ISSN: 1540-9538 [Electronic] United States
• PMID: 27217537 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Blohmke et al.

Chemical References

• Interferon Type I
• Interferon-gamma
• Tryptophan

Topics

• Adult
• Female
• Humans
• Immunomodulation
• Interferon Type I (blood, immunology)
• Interferon-gamma (blood, immunology)
• Male
• Middle Aged
• Salmonella typhi (immunology, metabolism)
• Tryptophan (biosynthesis, immunology)
• Typhoid Fever (blood, immunology, pathology)