The natural resistance-associated macrophage protein and susceptibility to intracellular pathogens

Over 20 years ago it was recognised that murine susceptibility to several antigenically unrelated pathogens was influenced by a host genetic factor. Linkage studies suggested that Lsh, Ity, and Bcg, the leishmania-, salmonella-, and mycobacteria-susceptibility genes, may be one gene, located on mouse chromosome 1. A reverse genetics strategy identified a candidate gene, Nramp1, which was expressed only in reticuloendothelial cells. A single nonconservative amino acid substitution was found to correlate with the susceptibility genotype in 27 inbred mouse strains. The production of an Nramp1 gene-disrupted mouse and a transgenic mouse, which restored the resistance genotype, conclusively proved that Nramp1 is the Bcg/Lsh/Ity gene. The Nramp family includes genes expressed in both prokaryotic and eukaryotic species. These genes have provided clues to the possible function of Nramp1. The ubiquitously expressed gene Nramp2 is an Fe(2+) transporter and a mutation in this gene causes microcytic anaemia in mice and rats. The functions of Nramp1 and its human homologue, NRAMP1, remain unknown, though it is hypothesised that they may regulate the intraphagosomal concentration of Fe(2+) and/or other cations. The identification of polymorphisms in the human NRAMP1 gene has facilitated studies on the relevance of this gene to human mycobacterial susceptibility. NRAMP1 variant alleles are strongly associated with tuberculosis, indicating that this is an important mycobacterial-susceptibility gene in humans and confirming the usefulness of this mouse model in the study of human infectious disease susceptibility.