Iron and malaria: the central role of hepcidin and macrophage function

Malaria is a global health problem affecting 300 to 500 milj, cases each year.
In malaria endemic areas anemia is an important public health problem leading
to increased morbidity and mortality mainly in cildren and pregnant women. The
anemia is mainly caused by malaria itself and iron deficiency. Treatment of
iron deficiency is therefore a priority of the WHO micronutrient program and
the efficacy of iron supplementation in the prevention and treatment of anemia
in malaria endemic regions has been demonstrated in multiple studies. However,
universal iron supplementation in settings with intense malaria transmission
may not be without risk, since iron may stimulate the growth of malaria
parasites and other microorganisms. So far, there is ongoing discussion on the
risk-benefit ratio of iron supplementation in malaria endemic regions. A recent
publication in the Lancet (Sazawal, 2006) showed the results of a large study
in Zanzibar that *routine supplementation with iron and folic acid in preschool
children in a population with high rates of malaria can result in an increased
risk of severe illness and death*. These findings emphasize the complex web of
serious interactions that exist between malaria, iron homeostasis, innate
immunity and iron supplementation and the need to unravel the underlying
mechanism of these interactions. The past decade has seen the identification
of new proteins involved in iron metabolism that has greatly increased the
insight in iron uptake and distribution. Especially the identification of the
central iron regulating hormone hepcidin has led to a shift in our perception
of iron homeostasis. Moreover insight in the important role of the
monocyte/macrophage in human iron homeostasis is increased.

In the current proposal, we propose an in vitro study to explore the
interaction of malaria infection, the parasitized erythrocyte, and monocyte
iron metabolism. We aim to study the role of hepcidin and to explore a) the
pathways involved in malaria induced alteration in monocyte hepcidin and b) the
intracellular iron content. Also the role of other iron regulatory proteins are
studied.

This proposol includes only in vitro experiments of (ex vivo) material of the
voluntary donor. By venapuncture 4 tot 6 tubes of 10 ml are drawn. In the
laboratory only monocytes are isolated and used for the experiments:
stimulation of monocytes with several stimuli including malaria infected
erythrocytes.

An once time only blooddonation, via a venapunction is asked from the volunteer
and the associated health risks are limited. Because of the puncture local
irritation, pain or hematoma can occur. Moreover 40 to 60 cc blood will be
withdrawn, although minimal to the amount of circulating blood, short
complaints of dizziness are light headiness can occur.
The volunteer has no contact nor any possibility of infection with the malaria
parasite. Moreover the outcome of this in vitro reserach will not lead to any
information about the volunteers healthstatus.