The Nramp1 protein and its role in resistance to infection and macrophage function

Susceptibility to infectious diseases is under genetic control in humans. A nimal models provide an ideal tool to study the genetic component of suscep tibility and to identify candidate genes that can then be tested for associ ation or linkage studies in human populations from endemic areas of disease . The Nramp1 gene was isolated by positional cloning the host resistance lo cus Bcg/Ity/Lsh, and mutations at this locus impair the resistance of mice to infections with intracellular parasites, such as Salmonella, Leishmania, and Mycobacterium. Allelic variants at the human Nramp1 homologue have rec ently been found to be associated with susceptibility to tuberculosis and l eprosy in humans. The Nramp1 protein is an integral membrane protein expres sed exclusively in the lysosomal compartment of monocytes and macrophages. After phagocytosis, Nramp1 is targeted to the membrane of the microbe-conta ining phagosome, where it may modify the intraphagosomal milieu to affect m icrobial replication. Although the biochemical mechanism of action of Nramp 1 at that site remains unknown, Nramp homologues have been identified in ma ny other animal species and actually define a protein family conserved from bacteria to humans. Some of these homologues have been shown to be divalen t cation transporters. Recently, a second member of the mammalian Nramp fam ily, Nramp2, was discovered and shown to be mutated in animal models of iro n deficiency. The Nramp2 protein was subsequently shown to be the major tra nsferrin-independent iron uptake system of the intestine. Together, these r esults suggest that Nramp1 may control intracellular microbial replication by actively removing iron or other divalent cations from the phagosomal spa ce.