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Grant Abstract

Grant Number: 5U01HD061246-02
PI Name: SWINKELS, DORINE W.
Project Title: IRON AND MALARIA: THE CENTRAL ROLE OF HEPCIDEN AND MACAROPHAGE FUNCTION

Abstract: DESCRIPTION (provided by applicant): The past decade has seen remarkable advances in our understanding of iron homeostasis, e.g. the discovery of hepcidin and other iron regulatory proteins, which may help to unravel the underlying mechanisms of the complex interaction between malaria, iron homeostasis and immune function. Based on these new insights and on recent findings of hepcidin expression in acute malaria and ex vivo human monocytes, the central hypothesis of this application is that malaria induces changes in iron regulatory proteins, including hepcidin, which subsequently affect monocyte/macrophage iron handling and innate immune responses. The goal of our application is to study how malaria influences iron regulatory proteins. This will provide leads for the development of new biomarkers for effective and safe iron supplementation and will increase our understanding of the development of some of the complications of iron supplementation. The specific aims of the current application are: 1. To obtain data from field studies whereby the influence of asymptomatic parasitemia or febrile P. vivax malaria on host iron homeostasis is explored. Both conditions follow a protracted course and hepcidin expression may influence the risk of anemia, the efficacy of iron supplementation and the incidence of infections with intracellular bacteria in malaria-endemic regions. Field studies will be carried out on the Indonesian Island Sumba, where P. falciparum and P. vivax are endemic. 2. To study the in vitro effects of P. falciparum on monocyte/macrophage iron regulatory proteins under different iron conditions and its interaction with innate immunity. Human monocytes will be incubated with cultured P. falciparum and its products and a variety of Toll like receptor agonists and blockers (to study pathways involved) with read outs on iron regulatory proteins on the mRNA level, protein level and functional level (intracellular iron contents, Salmonella killing and production of oxygen-derived radical species). PUBLIC HEALTH RELEVANCE: Anemia is an important public health problem and malaria and iron deficiency are common causes. Here we propose studies to elucidate the interaction between iron homeostasis and malaria to further optimize prevention, diagnostic and therapeutic strategies.

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