Research Article: Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans

Date Published: September 22, 2015

Publisher: Public Library of Science

Author(s): Thomas C. Darton, Christoph J. Blohmke, Eleni Giannoulatou, Claire S. Waddington, Claire Jones, Pamela Sturges, Craig Webster, Hal Drakesmith, Andrew J. Pollard, Andrew E. Armitage, Stephen Baker.

Abstract: BackgroundIron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge.Methodology/Principal FindingsFifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia.Conclusions/SignificanceWe demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi.

Partial Text: Typhoid fever is a common infection that follows oral ingestion and invasion of the Gram-negative bacterium Salmonella enterica serovar Typhi (S. Typhi). An estimated 26.9 million cases occurred globally in 2010, disproportionately affecting children in resource-limited areas of sub-Saharan Africa and southeastern Asia [1,2].

Salmonella Typhi is a significant human pathogen, leading to a major global burden of disease particularly among children and younger adults in endemic settings [1,2]. Evolution from a common Salmonella ancestor is thought to have occurred ~50–100,000 years ago [41]. However, the basis for the evolution of its ability to evade host defenses and cause systemic infection remains poorly characterized. Understanding how S. Typhi interacts with the human host environment, including the macrophage niche, is crucial in deciphering its pathogenicity and for devising prevention or eradication strategies. The battle for iron is a key determinant of host-bacterial interactions [8,9,31]. Here, using an experimental human typhoid challenge model, we track for the first time in an invasive human bacterial infection the behavior of the iron regulatory hormone hepcidin and its relationship to perturbations in iron parameters, inflammatory markers, and fever: significant hepcidin upregulation, accompanied by a profound decline in serum iron was observed in participants diagnosed with typhoid infection.



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