02856nas a2200433   4500000000100000008004100001260001700042653001200059653002100071653003000092653001200122653001900134653003800153653001100191653002100202653001400223653001800237653000900255653002600264653001400290653002600304653002200330653000900352653002500361653002200386653002100408653002900429653001700458653002500475100002200500700001600522700001300538700001100551245008800562300001000650490000800660520174000668022001402408       1999                            d  c1999 Jul-Aug10aAnimals10aCarrier Proteins10aCation Transport Proteins10aCations10aGene Frequency10aGenetic Predisposition to Disease10aHumans10aImmunity, Innate10aInfection10aIon Transport10aIron10aIron-Binding Proteins10aLysosomes10aMacrophage Activation10aMembrane Proteins10aMice10aMice, Inbred Strains10aModels, Molecular10aMultigene Family10aMycobacterium Infections10aPhagocytosis10aProtein Conformation1 aCanonne-Hergaux F1 aGruenheid S1 aGovoni G1 aGros P00aThe Nramp1 protein and its role in resistance to infection and macrophage function.  a283-90 v1113 a<p>Susceptibility to infectious diseases is under genetic control in humans. Animal models provide an ideal tool to study the genetic component of susceptibility and to identify candidate genes that can then be tested for association or linkage studies in human populations from endemic areas of disease. The Nramp1 gene was isolated by positional cloning the host resistance locus 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 recently been found to be associated with susceptibility to tuberculosis and leprosy in humans. The Nramp1 protein is an integral membrane protein expressed exclusively in the lysosomal compartment of monocytes and macrophages. After phagocytosis, Nramp1 is targeted to the membrane of the microbe-containing phagosome, where it may modify the intraphagosomal milieu to affect microbial replication. Although the biochemical mechanism of action of Nramp1 at that site remains unknown, Nramp homologues have been identified in many other animal species and actually define a protein family conserved from bacteria to humans. Some of these homologues have been shown to be divalent cation transporters. Recently, a second member of the mammalian Nramp family, Nramp2, was discovered and shown to be mutated in animal models of iron deficiency. The Nramp2 protein was subsequently shown to be the major transferrin-independent iron uptake system of the intestine. Together, these results suggest that Nramp1 may control intracellular microbial replication by actively removing iron or other divalent cations from the phagosomal space.</p>  a1081-650X