Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens

Nramp1 (natural resistance-associated macrophage protein one) regulates int racellular pathogen proliferation and macrophage inflammatory responses. Mu rine Nramp1 exhibits a natural polymorphism with alleles termed resistant a nd susceptible. Alleles restrict or allow the proliferation of intracellula r pathogens, respectively. Structural predictions suggest that Nramp1 encod es the prototypic member of a transporter family. Nramp1 exhibits sequence identity to Nramp2, which regulates intestinal and reticulocyte iron uptake . Based on this sequence identity we have initiated experiments for Nramp1 to investigate its role in macrophage iron homoeostasis and using a transfe ction approach in the RAW264.7 murine macrophage-like cell Line, which lack s a functional Nramp2 gene, Nramp1 expression supports increased acute cyto plasmic influx of iron, detected using the fluorescent iron sensor dye calc ein, Analysis of the endogenous iron sensors, iron regulatory protein 1 and 2, reveals a greater flux of iron in Nramp1-expressing cells and in its ex clusion from the cytoplasm, Other work supports the prediction that Nramp1 is a phosphoprotein and the extent of phosphorylation changes in response t o inflammatory cytokines. Together these data support the hypothesis that c ontrol of intracellular iron homoeostasis is a vital element used by phagoc ytes to control the proliferation of intracellular pathogens.