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

Blohmke, CJ; Darton, TC; Jones, C; Suarez, NM; Waddington, CS; Angus, B; Zhou, L; Hill, J; Clare, S; Kane, L; et al. Blohmke, CJ; Darton, TC; Jones, C; Suarez, NM; Waddington, CS; Angus, B; Zhou, L; Hill, J; Clare, S; Kane, L; Mukhopadhyay, S; Schreiber, F; Duque-Correa, MA; Wright, JC; Roumeliotis, TI; Yu, L; Choudhary, JS; Mejias, A; Ramilo, O; Shanyinde, M; Sztein, MB; Kingsley, RA; Lockhart, S; Levine, MM; Lynn, DJ; Dougan, G; Pollard, AJ (2016) Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever. The Journal of Experimental Medicine, 213 (6). pp. 1061-1077. ISSN 0022-1007 https://doi.org/10.1084/jem.20151025
SGUL Authors: Zhou, Li Qing

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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.

Item Type: Article
Additional Information: © Blohmke et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Keywords: Immunology, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: The Journal of Experimental Medicine
ISSN: 0022-1007
Dates:
DateEvent
23 May 2016Published
8 April 2016Accepted
Projects:
Project IDFunderFunder ID
092661Wellcome Trusthttp://dx.doi.org/10.13039/100004440
M02637X/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIEDEuropean Molecular Biology Organizationhttp://dx.doi.org/10.13039/100004410
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
UNSPECIFIEDNational Institute of Allergy and Infectious Diseaseshttp://dx.doi.org/10.13039/100000060
R01 AI-036525National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U-19 AI-082655National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U19-AI109776National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U-19 AI089987National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U-19 AI057234National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U01 AI82210National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UNSPECIFIEDPublic Health Englandhttp://dx.doi.org/10.13039/501100002141
URI: https://openaccess.sgul.ac.uk/id/eprint/108164
Publisher's version: https://doi.org/10.1084/jem.20151025

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