RESUMO
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.
Assuntos
Proteínas de Transporte/fisiologia , Proteínas de Transporte de Cátions , Predisposição Genética para Doença/genética , Imunidade Inata/genética , Proteínas de Ligação ao Ferro , Ativação de Macrófagos/efeitos dos fármacos , Proteínas de Membrana/fisiologia , Animais , Proteínas de Transporte/genética , Cátions/metabolismo , Frequência do Gene , Humanos , Infecções/genética , Infecções/imunologia , Transporte de Íons/genética , Ferro/metabolismo , Lisossomos/fisiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Família Multigênica , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Fagocitose/genética , Conformação ProteicaRESUMO
The identification and characterization of genetic factors influencing natural susceptibility to infectious diseases in humans and in model organisms, such as the laboratory mouse, can provide new insight into the basic mechanisms of host defense against infections. In the mouse, resistance or susceptibility to infection with intracellular pathogens such as Salmonella, Mycobacterium and Leishmnania is controlled by the Natural resistance associated macrophage protein (Nramp1) gene on chromosome 1, which influences the rate of intracellular replication of these parasites in macrophages. Nramp1 codes for an integral membrane protein, which is expressed exclusively in macrophage/monocytes and polymorphonuclear leukocytes. The protein is localized to the endosomal/lysosomal compartment of the macrophage and is rapidly recruited to the membrane of the particle-containing phagosome upon phagocytosis. Nramp defines a novel family of functionally related membrane proteins including Nramp2, which was recently shown to be the major transferrin-independent uptake system of the intestine in mammals. This observation supports the hypothesis that the phagocyte-specific Nramp1 protein may regulate the intraphagosomal replication of antigenically unrelated bacteria by controlling divalent cation concentrations at that site. Recent genetic studies have found that allelic variants at the human NRAMP1 locus are associated with susceptibility to leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis) and possibly with the onset of rheumatoid arthritis.
Assuntos
Infecções Bacterianas/fisiopatologia , Proteínas de Transporte/fisiologia , Proteínas de Transporte de Cátions , Imunidade Inata/fisiologia , Leishmaniose/imunologia , Macrófagos/fisiologia , Proteínas de Membrana/fisiologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Humanos , Imunidade Inata/genética , Macrófagos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
The scope of the tuberculosis (TB) epidemic in the world today is enormous, with about 30 million active cases. Current research into preventing the spread of TB is focused on development of new drugs to inactivate Mycobacterium tuberculosis, the causative agent of TB, as well as on identifying the critical steps of host defense to infection with Mycobacteria, which might also yield therapeutic targets. Our infection genomics approach toward the latter strategy has been to isolate and characterize a mouse gene, Bcg (Nramp1), which controls natural susceptibility to infection with Mycobacteria, as well as Salmonella and Leishmania. Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Imunidade Inata/genética , Hanseníase/genética , Macrófagos/imunologia , Proteínas de Membrana/genética , Tuberculose/genética , Alelos , Animais , Antituberculosos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/prevenção & controle , Surtos de Doenças , Suscetibilidade a Doenças/imunologia , Ligação Genética , Predisposição Genética para Doença , Genoma Bacteriano , Genoma Humano , Genoma de Protozoário , Saúde Global , Humanos , Leishmaniose/genética , Leishmaniose/imunologia , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/imunologia , Hanseníase/prevenção & controle , Camundongos , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Tuberculose/prevenção & controleRESUMO
The Mendelian segregation of resistance to infection in different strains of mice infected with mycobacteria, Salmonella and Leishmania spp, all of which live in macrophages, is currently under close scrutiny. Here, Erwin Schurr and colleagues review the nature and function of the Bcg gene in controlling innate resistance to mycobacterial infection in mice and speculate on the occurrence of a possible human equivalent.
Assuntos
Ativação de Macrófagos , Infecções por Mycobacterium/genética , Animais , Mapeamento Cromossômico , Regulação da Expressão Gênica , Genes Dominantes , Marcadores Genéticos , Humanos , Imunidade Inata/genética , Hanseníase/genética , Hanseníase/imunologia , Macrófagos/fisiologia , Camundongos/genética , Camundongos/imunologia , Camundongos/microbiologia , Infecções por Mycobacterium/imunologia , Fenótipo , Tuberculose/genética , Tuberculose/imunologiaRESUMO
In the mouse, innate resistance or susceptibility to infection with numerous mycobacteria is controlled by the Bcg host resistance locus located on the centromeric region of chromosome 1. The resistance/susceptibility phenotype is expressed by the mature tissue macrophage and Bcg has been identified as a locus that is involved in the regulation of macrophage activation and in the modulation of acquired immune responses to mycobacteria. Experiments aimed at the cloning of the Bcg gene via a "reverse genetics" approach have generated a detailed genetic map in the immediate vicinity of the locus, placing Bcg within the reach of long-range eukaryotic cloning techniques. The chromosomal segment around Bcg in the mouse is exactly conserved onto the long arm (q) of human chromosome 2. Linkage of genetic markers from human chromosome 2q with susceptibility to leprosy or tuberculosis would support both the existence of a susceptibility gene in humans and the contention that this susceptibility gene is a homologue of the mouse Bcg locus.
Assuntos
Modelos Animais de Doenças , Camundongos/genética , Infecções por Mycobacterium/genética , Animais , Ligação Genética , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Camundongos/imunologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/veterinária , Mycobacterium bovis/genética , Homologia de Sequência do Ácido NucleicoRESUMO
Mice of different inbred strains vary in their resistance to intravenous infection with Mycobacterium lepraemurium (MLM). The mean survival time of MLM-infected A/J and DBA/2 mice is significantly longer than that of similarly infected C57BL/6 and BALB/c mice. The typing of AXB/BXA recombinant inbred strains (A = A/J,B = C57BL/6) for the trait of relative resistance/susceptibility to MLM revealed a perfect match with the strain distribution pattern of resistance/susceptibility to Mycobacterium bovis (BCG), the trait which is controlled by the Bcg (Ity, Lsh) locus on chromosome 1. The control, by this gene, of response to MLM was further confirmed by the demonstration that BALB/c-Bcgr congenic mice, which carry the DBA/2-derived Bcgr (resistant) allele on chromosome 1, are significantly more resistant to MLM infection than their BALB/c (Bcgs, susceptible) counterparts.