title: Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans.
abstract: BACKGROUND
  Iron 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.
  
  
  RESULTS
  Fifty 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
  We 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.
authors.affiliation: Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
authors.affiliation: Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Biochemistry, Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, United Kingdom.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sturges
authors.affiliation: Department of Biochemistry, Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, United Kingdom.
authors.forename: Craig
authors.initials: C
authors.lastname: Webster
authors.affiliation: BRC Blood Theme, NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Hal
authors.initials: H
authors.lastname: Drakesmith
authors.affiliation: Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Armitage
mesh_terms: D000293:Adolescent; D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis; D016207:Cytokines / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood; D005334:Fever; D064368:Healthy Volunteers; D064451:Hepcidins / Q000097:blood*; D006801:Humans; D007113:Immunity, Innate; D007501:Iron / Q000097:blood*; D008297:Male; D008875:Middle Aged; D044967:Serum / Q000737:chemistry*; D014435:Typhoid Fever / Q000276:immunology* / Q000473:pathology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D064451:Hepcidins; D002097:C-Reactive Protein; D005293:Ferritins; D007501:Iron