Both, mammalian cells and microbes have an essential need for iron, which is required for many metabolic processes and for microbial pathogenicity. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. Cytokines and the acute phase protein hepcidin affect iron homeostasis leading to the retention of the metal within macrophages and hypoferremia. This is considered to result from a defense mechanism of the body to limit the availability of iron for extracellular pathogens while on the other hand the reduction of circulating iron results in the development of anemia of inflammation. Opposite, iron and the erythropoiesis inducing hormone erythropoietin affect innate immune responses by influencing IFN- mediated (iron) or NF-kB inducible (erythropoietin) immune effector pathways in macrophages. Thus, macrophages loaded with iron lose their ability to kill intracellular pathogens via IFN- mediated effector pathways such as nitric oxide (NO) formation. Accordingly, macrophages invaded by the intracellular bacteria Salmonella enterica serovar Typhimurium increase the expression of the iron export protein ferroportin thereby reducing the availability of iron for intramacrophage bacteria while on the other side strengthening anti-microbial macrophage effector pathways via increased formation of NO or TNF-. In addition, certain innate resistance genes such as natural resistance associated macrophage protein function (Nramp1) or lipocalin-2 exert part of their antimicrobial activity by controlling host and/or microbial iron homeostasis. Consequently, pharmacological or dietary modification of cellular iron trafficking enhances host resistance to intracellular pathogens but may increase susceptibility to microbes in the extracellular compartment and vice versa. Thus, the control over iron homeostasis is a central battlefield in host-pathogen interplay influencing the course of an infectious disease.

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Iron at the interface of immunity and infection

Purpose of reviewAnemia is prevalent in patients with infections and other inflammatory conditions. Induction of the iron regulatory hormone hepcidin has been implicated in the pathogenesis of anemia of inflammation. This review outlines recent discoveries in understanding how hepcidin and its recep

Hepcidin regulation in the anemia of inflammation.

In light of evidence that high-dose iron supplements lead to a range of adverse events in low-income settings, the safety and efficacy of lower doses of iron provided through biological or industrial fortification of foodstuffs is reviewed. First, strategies for point-of-manufacture chemical fortification are compared with biofortification achieved through plant breeding. Recent insights into the mechanisms of human iron absorption and regulation, the mechanisms by which iron can promote malaria and bacterial infections, and the role of iron in modifying the gut microbiota are summarized. There is strong evidence that supplemental iron given in nonphysiological amounts can increase the risk of bacterial and protozoal infections (especially malaria), but the use of lower quantities of iron provided within a food matrix, ie, fortified food, should be safer in most cases and represents a more logical strategy for a sustained reduction of the risk of deficiency by providing the best balance of risk and benefits. Further research into iron compounds that would minimize the availability of unabsorbed iron to the gut microbiota is warranted.

/pdf/dietary-strategies-for-improving-iron-status-balancing-55qb9qpyz6.pdf

Dietary strategies for improving iron status: balancing safety and efficacy.

Malaria and iron have a complex but important relationship. Plasmodium proliferation requires iron, both during the clinically silent liver stage of growth and in the disease-associated phase of erythrocyte infection. Precisely how the protozoan acquires its iron from its mammalian host remains unclear, but iron chelators can inhibit pathogen growth in vitro and in animal models. In humans, iron deficiency appears to protect against severe malaria, while iron supplementation increases risks of infection and disease. Malaria itself causes profound disturbances in physiological iron distribution and utilization, through mechanisms that include hemolysis, release of heme, dyserythropoiesis, anemia, deposition of iron in macrophages, and inhibition of dietary iron absorption. These effects have significant consequences. Malarial anemia is a major global health problem, especially in children, that remains incompletely understood and is not straightforward to treat. Furthermore, the changes in iron metabolism during a malaria infection may modulate susceptibility to co-infections. The release of heme and accumulation of iron in granulocytes may explain increased vulnerability to non-typhoidal Salmonella during malaria. The redistribution of iron away from hepatocytes and into macrophages may confer host resistance to superinfection, whereby blood-stage parasitemia prevents the development of a second liver-stage Plasmodium infection in the same organism. Key to understanding the pathophysiology of iron metabolism in malaria is the activity of the iron regulatory hormone hepcidin. Hepcidin is upregulated during blood-stage parasitemia and likely mediates much of the iron redistribution that accompanies disease. Understanding the regulation and role of hepcidin may offer new opportunities to combat malaria and formulate better approaches to treat anemia in the developing world.

/pdf/iron-anemia-and-hepcidin-in-malaria-209mybla51.pdf

Iron, anemia and hepcidin in malaria

Cohort Profile: The Kiang West Longitudinal Population Study (KWLPS)—a platform for integrated research and health care provision in rural Gambia Branwen J Hennig, Stefan A Unger, Bai Lamin Dondeh, Jahid Hassan, Sophie Hawkesworth, Landing Jarjou, Kerry S Jones, Sophie E Moore, Helen M Nabwera, Mohammed Ngum, Ann Prentice, Bakary Sonko, Andrew M Prentice* and Anthony J Fulford MRC International Nutrition Group at MRC Unit The Gambia, Banjul, The Gambia, MRC International Nutrition Group, London School of Hygiene & Tropical Medicine, London, UK, University of Edinburgh, Department of Child Life and Health, Edinburgh, UK, MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK and Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, UK These authors contributed equally to this work. *Corresponding author. MRC International Nutrition Group at LSHTM, UK & MRC Unit, The Gambia, Keppel Street, London WC1E 7HT, UK. E-mail: Andrew.prentice@lshtm.ac.uk

/pdf/cohort-profile-the-kiang-west-longitudinal-population-study-tzosb9fu01.pdf

Cohort Profile: The Kiang West Longitudinal Population Study (KWLPS)-a platform for integrated research and health care provision in rural Gambia

Sarah H. Atkinson*, Andrew E. Armitage*, Shivani Khandwala, Tabitha W. Mwangi, Sophie Uyoga, Philip A. Bejon, Thomas N. Williams, Andrew M. Prentice, Hal Drakesmith Department of Paediatrics, Oxford University Hospitals, University of Oxford, Oxford, UK. Oxford University Clinical Academic Graduate School, Oxford, UK. Kenya Medical Research Institute/Wellcome Trust Research Programme, Centre of Geographic Medicine Research-Coast, Kilifi District Hospital, Kilifi, Kenya. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford University Hospitals, UK. Department of Medicine, Imperial College, London, UK. MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London, UK and MRC Keneba, The Gambia.

Combinatorial effects of malaria season, iron deficiency and inflammation determine plasma hepcidin concentration in African children Running head: Hepcidin and malaria season

This dataset contains demographic information and results of lab assays for a cohort of 780 Gambian children. The study was conducted at the start (July 2001) and end (December 2001/January 2002) of a malaria season. The variables presented in this dataset were used in the analysis of a related manuscript that will be submitted at the Wellcome Open Research.

Sarah H. Atkinson

Papers

Combinatorial effects of malaria season, iron deficiency and inflammation determine plasma hepcidin concentration in African children Running head: Hepcidin and malaria season

Replication Data for: Interferon-gamma polymorphisms and risk of iron deficiency and anaemia in Gambian children

anemic African children Hepcidin is the major predictor of erythrocyte iron incorporation in

deficiency anemia in West African children Tumor necrosis factor SNP haplotypes are associated with iron