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

Blohmke, Christoph J.; Darton, Thomas C.; Jones, Claire; Suárez, Nicolás M.; Waddington, Claire S.; Angus, Brian; Zhou, Lei; Hill, Jennifer; Clare, Simon; Kane, Leanne; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Duque-Correa, María A.; Wright, James C.; Roumeliotis, Theodoros I.; Yu, Lu; Choudhary, Jyoti S.; Mejías, Asunción; Ramilo, Octavio; Shanyinde, Milensu; Sztein, Marcelo B.; Kingsley, Robert A.; Lockhart, Stephen; Levine, Myron M.; Lynn, David J.; Dougan, Gordon; Pollard, Andrew J.

doi:10.1084/jem.20151025

Cited by 46 publications

(73 citation statements)

References 56 publications

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“…Similar results were observed in studies performed in chimpanzees 39 . Our culture-PCR results suggest that S. Typhi DNA is detectable in blood within 48 h after ingestion; data that are supported by corresponding increases in plasma cytokines and host gene expression activity 40 . Factors affecting the outcome of these early invasion events, which probably occur more frequently than was recognised here as demonstrated by the ubiquitous cytokine signature found in challenged participants, are uncertain but probably include the host inflammatory responses and early immune responses.…”

Section: Discussionsupporting

confidence: 90%

Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia

Darton

Zhou

Blohmke

et al. 2017

Journal of Infection

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SummaryBackgroundImproved diagnostics for typhoid are needed; a typhoid controlled human infection model may accelerate their development and translation. Here, we evaluated a blood culture-PCR assay for detecting infection after controlled human infection with S. Typhi and compared test performance with optimally performed blood cultures.Methodology/Principal findingsCulture-PCR amplification of blood samples was performed alongside daily blood culture in 41 participants undergoing typhoid challenge. Study endpoints for typhoid diagnosis (TD) were fever and/or bacteraemia. Overall, 24/41 (59%) participants reached TD, of whom 21/24 (86%) had ≥1 positive blood culture (53/674, 7.9% of all cultures) or 18/24 (75%) had ≥1 positive culture-PCR assay result (57/684, 8.3%). A further five non-bacteraemic participants produced culture-PCR amplicons indicating infection; overall sensitivity/specificity of the assay compared to the study endpoints were 70%/65%. We found no significant difference between blood culture and culture-PCR methods in ability to identify cases (12 mismatching pairs, p = 0.77, binomial test). Clinical and stool culture metadata demonstrated that additional culture-PCR amplification positive individuals likely represented true cases missed by blood culture, suggesting the overall attack rate may be 30/41 (73%) rather than 24/41 (59%). Several participants had positive culture-PCR results soon after ingesting challenge providing new evidence for occurrence of an early primary bacteraemia.Conclusions/SignificanceOverall the culture-PCR assay performed well, identifying extra typhoid cases compared with routine blood culture alone. Despite limitations to widespread field-use, the benefits of increased diagnostic yield, reduced blood volume and faster turn-around-time, suggest that this assay could enhance laboratory typhoid diagnostics in research applications and high-incidence settings.

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Section: Discussionsupporting

confidence: 90%

Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia

Darton

Zhou

Blohmke

et al. 2017

Journal of Infection

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“…In fact, IFNγ-induced IDO1 expression seems to be protective in Toxoplasma gondii, Salmonella enterica serovar Typhi ( S . Typhi), or Chlamydia pneumoniae infections (124, 125). For example, IFNγ-primed macrophages effectively contain intracellular replication of S .…”

Section: Amino Acid Metabolism and Ifnsmentioning

confidence: 99%

“…For example, IFNγ-primed macrophages effectively contain intracellular replication of S . Typhi depending on the activation of IDO1 (125). …”

Section: Amino Acid Metabolism and Ifnsmentioning

confidence: 99%

“…Similarly, genetic ablation of IDO1 or chemical inhibition with 1-methyl- d - l -tryptophan suppresses viral replication of murine leukemia virus in vivo and upregulates type I IFN production (128). In conclusion, in various chronic infections, autoimmune diseases, and cancer, an increased expression of IDO1, besides its antiviral effects, may promote an immunosuppressive environment, which potentially contributes to disease (119, 121, 123, 125). …”

Section: Amino Acid Metabolism and Ifnsmentioning

confidence: 99%

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Effects of Interferons and Viruses on Metabolism

2016

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Interferons (IFNs) are potent pleiotropic cytokines that broadly alter cellular functions in response to viral and other infections. These alterations include changes in protein synthesis, proliferation, membrane composition, and the nutritional microenvironment. Recent evidence suggests that antiviral responses are supported by an IFN-induced rewiring of the cellular metabolism. In this review, we discuss the roles of type I and type II IFNs in regulating the cellular metabolism and biosynthetic reactions. Furthermore, we give an overview of how viruses themselves affect these metabolic activities to promote their replication. In addition, we focus on the lipid as well as amino acid metabolisms, through which IFNs exert potent antiviral and immunomodulatory activities. Conversely, the expression of IFNs is controlled by the nutrient sensor mammalian target of rapamycin or by direct reprograming of lipid metabolic pathways. These findings establish a mutual relationship between IFN production and metabolic core processes.

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“…Nevertheless, thorough screening of potential research participants' social backgrounds to ensure they do not have any regular contact during the study period with individuals deemed at high risk of RSV-related complications should be mandatory. In contrast to experimental challenge with human rhinovirus [13] and bacterial pathogens such as Salmonella typhi [15] (which have all been carried out as out-patient studies), all contemporary experimental human RSV challenge studies have been carried out using in-patient quarantine to further isolate infected individuals from the community at large for the period of highest potential infectivity. Whether this is absolutely necessary remains unclear.…”

Section: Logistical and Ethical Issues In Deliberately Infecting Withmentioning

confidence: 99%

Controlled human infection with RSV: The opportunities of experimental challenge

Habibi

Chiu

2017

Vaccine

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

Abstract: Work in humans and mice highlights the role of tryptophan metabolism in the immunopathogenesis of typhoid fever, offering novel insight into clinical disease.

Cited by 46 publications

References 56 publications

Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia

Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia

Effects of Interferons and Viruses on Metabolism

Controlled human infection with RSV: The opportunities of experimental challenge

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