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PMID: 7650477 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene.

The Journal of experimental medicine ·Vol. 182 ·No. 3 ·1995-09-01 ·Pages 655-66

Vidal S, Tremblay ML, Govoni G, Gauthier S, Sebastiani G, Malo D, Skamene E, Olivier M, Jothy S, Gros P

Abstract

In mice, natural resistance or susceptibility to infection with intracellular parasites is determined by a locus or group of loci on chromosome 1, designated Bcg, Lsh, and Ity, which controls early microbial replication in reticuloendothelial organs. We have identified by positional cloning a candidate gene for Bcg, Nramp1, which codes for a novel macrophage-specific membrane transport protein. We have created a mouse mutant bearing a null allele at Nramp1, and we have analyzed the effect of such a mutation on natural resistance to infection. Targeted disruption of Nramp1 has pleiotropic effects on natural resistance to infection with intracellular parasites, as it eliminated resistance to Mycobacterium bovis, Leishmania donovani, and lethal Salmonella typhimurium infection, establishing that Nramp1, Bcg, Lsh, and Ity are the same locus. Comparing the profiles of parasite replication in control and Nramp1-/- mice indicated that the Nramp1Asp169 allele of BcgS inbred strains is a null allele, pointing to a critical role of this residue in the mechanism of action of the protein. Despite their inability to control parasite growth in the early nonimmune phase of the infection, Nramp1-/- mutants can overcome the infection in the late immune phase, suggesting that Nramp1 plays a key role only in the early part of the macrophage-parasite interaction and may function by a cytocidal or cytostatic mechanism distinct from those expressed by activated macrophages.

Related Genes
Bcg Ity Lsh Nramp1
MeSH Terms
Alleles Animals Carrier Proteins/genetics,physiology Cation Transport Proteins Cells, Cultured Chimera Crosses, Genetic Female Genes Humans Immunity, Innate/genetics Infant, Newborn Leishmania donovani Leishmaniasis, Visceral/genetics,immunology Male Membrane Proteins/genetics,physiology Mice Mice, Inbred BALB C Mice, Knockout Mycobacterium bovis Phenotype Point Mutation Salmonella Infections, Animal/genetics,immunology Salmonella typhimurium Stem Cell Transplantation T-Lymphocytes/immunology Tuberculosis/genetics,immunology
Chemicals
Carrier Proteins Cation Transport Proteins Membrane Proteins natural resistance-associated macrophage protein 1
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Vidal S
Department of Biochemistry, McGill University, Montreal, Québec, Canada.
Tremblay M L
Govoni G
Gauthier S
Sebastiani G
Malo D
Skamene E
Olivier M
Jothy S
Gros P
References (60)
60 references, click to expand
  1. Genetically conferred defect in anti-Salmonella antibody formation renders CBA/N mice innately susceptible to Salmonella typhimurium infection.
    J Immunol. 1981 Apr;126(4):1368-72 PMID: 7009738
  2. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.
    Biochemistry. 1979 Nov 27;18(24):5294-9 PMID: 518835
  3. Genetic regulation of resistance to intracellular pathogens.
    Nature. 1982 Jun 10;297(5866):506-9 PMID: 7045675
  4. Control of early Salmonella typhimurium growth in innately Salmonella-resistant mice does not require functional T lymphocytes.
    J Immunol. 1982 Oct;129(4):1349-51 PMID: 7050243
  5. Immunopathology of BCG infection in genetically resistant and susceptible mouse strains.
    J Immunol. 1982 Nov;129(5):2179-85 PMID: 6749986
  6. Cellular mechanisms of genetically controlled host resistance to Mycobacterium bovis (BCG).
    J Immunol. 1983 Oct;131(4):1966-72 PMID: 6311901
  7. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity.
    Anal Biochem. 1983 Jul 1;132(1):6-13 PMID: 6312838
  8. Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-gamma is the activating lymphokine.
    J Clin Invest. 1983 Oct;72(4):1506-10 PMID: 6415111
  9. Genetic control of the innate resistance of mice to Salmonella typhimurium: expression of the Ity gene in peritoneal and splenic macrophages isolated in vitro.
    J Immunol. 1983 Dec;131(6):3006-13 PMID: 6358358
  10. Phenotypic expression of genetically-controlled natural resistance to Mycobacterium bovis (BCG).
    J Immunol. 1984 Feb;132(2):888-92 PMID: 6361135
  11. Regulation of resistance to leprosy by chromosome 1 locus in the mouse.
    Immunogenetics. 1984;19(2):117-24 PMID: 6365754
  12. Transfer of innate resistance and susceptibility to Leishmania donovani infection in mouse radiation bone marrow chimaeras.
    Immunology. 1984 Jul;52(3):417-22 PMID: 6378765
  13. Evidence for inhibition of fusion of lysosomal and prelysosomal compartments with phagosomes in macrophages infected with pathogenic Mycobacterium avium.
    Infect Immun. 1986 Apr;52(1):252-62 PMID: 2870027
  14. Susceptibilities of macrophage populations to infection in vitro by Leishmania donovani.
    Infect Immun. 1987 Feb;55(2):467-71 PMID: 3804446
  15. Experimental visceral leishmaniasis: production of interleukin 2 and interferon-gamma, tissue immune reaction, and response to treatment with interleukin 2 and interferon-gamma.
    J Immunol. 1987 Apr 1;138(7):2290-7 PMID: 3104456
  16. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells.
    Cell. 1987 Nov 6;51(3):503-12 PMID: 2822260
  17. Regulation of host resistance to Mycobacterium intracellulare in vivo and in vitro by the Bcg gene.
    Immunogenetics. 1989;30(3):218-21 PMID: 2673999
  18. Macrophage-parasite interactions in Leishmania infections.
    J Leukoc Biol. 1990 Feb;47(2):187-93 PMID: 2406358
  19. Parasitophorous vacuoles of Leishmania amazonensis-infected macrophages maintain an acidic pH.
    Infect Immun. 1990 Mar;58(3):779-87 PMID: 1689700
  20. The role of activated macrophages in protection and immunopathology in tuberculosis.
    Res Microbiol. 1990 Feb;141(2):253-6 PMID: 2111928
  21. Activation of tuberculostatic macrophage functions by gamma interferon, interleukin-4, and tumor necrosis factor.
    Infect Immun. 1990 Aug;58(8):2675-7 PMID: 2115027
  22. crnA encodes a nitrate transporter in Aspergillus nidulans.
    Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):204-8 PMID: 1986367
  23. Inhibition of macrophage phagosome-lysosome fusion by Salmonella typhimurium.
    Infect Immun. 1991 Jul;59(7):2232-8 PMID: 2050395
  24. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene.
    Nature. 1992 Jun 4;357(6377):407-10 PMID: 1594045
  25. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.
    Cell. 1992 Jun 12;69(6):915-26 PMID: 1606615
  26. Influence of H-2 genes on growth of Mycobacterium tuberculosis in the lungs of chronically infected mice.
    Immunology. 1992 May;76(1):129-32 PMID: 1628890
  27. Genomic DNA microextraction: a method to screen numerous samples.
    Anal Biochem. 1992 Mar;201(2):331-5 PMID: 1632522
  28. Targeting of the T-cell receptor zeta-chain gene in embryonic stem cells: strategies for generating multiple mutations in a single gene.
    Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9929-33 PMID: 1409721
  29. Assignment of the genes encoding human interleukin-8 receptor types 1 and 2 and an interleukin-8 receptor pseudogene to chromosome 2q35.
    Genomics. 1992 Nov;14(3):685-91 PMID: 1427896
  30. Salmonella typhimurium activates virulence gene transcription within acidified macrophage phagosomes.
    Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10079-83 PMID: 1438196
  31. Functional interactions between putative intramembrane charged residues in the lactose permease of Escherichia coli.
    Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10547-51 PMID: 1438245
  32. Resistance of inbred mice to Salmonella typhimurium.
    J Infect Dis. 1972 Oct;126(4):378-86 PMID: 4403914
  33. Genetics of resistance to infection with Salmonella typhimurium in mice.
    J Infect Dis. 1976 Jan;133(1):72-8 PMID: 1107437
  34. Regulation of Leishmania populations within the host. II. genetic control of acute susceptibility of mice to Leishmania donovani infection.
    Clin Exp Immunol. 1977 Oct;30(1):130-40 PMID: 606434
  35. Phagolysosome formation, cyclic adenosine 3':5'-monophosphate and the fate of Salmonella typhimurium within mouse peritoneal macrophages.
    J Gen Microbiol. 1979 Feb;110(2):421-9 PMID: 220378
  36. Locating salmonella resistance gene on mouse chromosome 1.
    Clin Exp Immunol. 1979 Jul;37(1):1-6 PMID: 385184
  37. Regulation of Leishmania populations within the host. IV. Parasite and host cell kinetics studied by radioisotope labelling.
    Acta Trop. 1979 Jun;36(2):171-9 PMID: 41426
  38. Intracellular trafficking and the parasitophorous vacuole of Leishmania mexicana-infected macrophages.
    J Cell Sci. 1992 Dec;103 ( Pt 4):1193-210 PMID: 1487496
  39. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg.
    Cell. 1993 May 7;73(3):469-85 PMID: 8490962
  40. High-resolution linkage map in the vicinity of the host resistance locus Bcg.
    Genomics. 1993 Jun;16(3):655-63 PMID: 8100801
  41. Lipopolysaccharide nonresponder cells: the C3H/HeJ defect.
    Immunobiology. 1993 Apr;187(3-5):257-71 PMID: 8330899
  42. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes.
    Science. 1993 Jul 16;261(5119):355-8 PMID: 8332900
  43. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice.
    Science. 1993 Jul 16;261(5119):358-61 PMID: 8332901
  44. Physical delineation of the minimal chromosomal segment encompassing the murine host resistance locus Bcg.
    Genomics. 1993 Sep;17(3):667-75 PMID: 8244383
  45. Disseminated tuberculosis in interferon gamma gene-disrupted mice.
    J Exp Med. 1993 Dec 1;178(6):2243-7 PMID: 8245795
  46. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection.
    J Exp Med. 1993 Dec 1;178(6):2249-54 PMID: 7504064
  47. Identification, chromosomal location, and genome organization of mammalian G-protein-coupled receptors.
    Genomics. 1993 Nov;18(2):175-84 PMID: 8288218
  48. The murine homologue of the human interleukin-8 receptor type B maps near the Ity-Lsh-Bcg disease resistance locus.
    Genomics. 1993 Nov;18(2):410-3 PMID: 8288247
  49. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.
    Science. 1994 Feb 4;263(5147):678-81 PMID: 8303277
  50. Cytokines and tuberculosis.
    J Leukoc Biol. 1994 May;55(5):676-81 PMID: 8182346
  51. Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium-infected macrophages.
    J Immunol. 1994 Sep 15;153(6):2568-78 PMID: 8077667
  52. An Nramp-related sequence maps to mouse chromosome 17.
    Mamm Genome. 1994 Jul;5(7):458-60 PMID: 7919662
  53. Genetic control of host resistance to infection.
    Trends Genet. 1994 Oct;10(10):365-71 PMID: 7985241
  54. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites.
    Genomics. 1994 Sep 1;23(1):51-61 PMID: 7829102
  55. Two mammalian cell internalization strategies used by pathogenic bacteria.
    Annu Rev Genet. 1994;28:395-422 PMID: 7893133
  56. Genetic and physical mapping of 2q35 in the region of the NRAMP and IL8R genes: identification of a polymorphic repeat in exon 2 of NRAMP.
    Genomics. 1994 Nov 15;24(2):295-302 PMID: 7698752
  57. Identification and characterization of a second mouse Nramp gene.
    Genomics. 1995 Jan 20;25(2):514-25 PMID: 7789986
  58. Mapping of genes controlling Leishmania major infection in CXS recombinant inbred mice.
    Eur J Immunogenet. 1993 Oct;20(5):349-62 PMID: 9098403
  59. Influence of H-2 complex on acquired resistance to Leishmania donovani infection in mice.
    Nature. 1980 Jan 3;283(5742):72-4 PMID: 6765984
  60. Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice.
    J Immunol. 1981 Dec;127(6):2417-21 PMID: 6795274
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.182.3.655
Published
1995-09-01
Pages
655-66
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2192162
Subset
IM
Grants
NIAID NIH HHS · 5R01 AI35237.02 · United States
External Links
PubMed source DOI: 10.1084/jem.182.3.655 PMC Full Text View journal details
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