Disease relevance of Slc11a1

• Influence of Slc11a1 on the outcome of Salmonella enterica serovar Enteritidis infection in mice is associated with Th polarization [1].
• Disruption of the Nramp1 (also known as Slc11a1) gene in Kupffer cells attenuates early-phase, warm ischemia-reperfusion injury in the mouse liver [2].
• To investigate the molecular pathogenesis of infectious disease susceptibility, we compared the behaviour of heterologously and endogenously expressed wild-type and mutant Slc11a1 by immunofluorescence, immunoelectron microscopy and Western-blot analysis [3].
• Myeloproliferation in BXH-2 mice is concomitant to increased susceptibility to Mycobacterium bovis (BCG) despite the presence of resistance alleles at the Nramp1 locus [4].
• Analysis of genomic cosmid and bacteriophage clones overlapping the complete Nramp1 gene revealed that the gene was composed of 15 exons and spanned 11.5 kb of genomic DNA [5].

Psychiatry related information on Slc11a1

• We propose that acquisition of SPI2 by S. enterica not only enabled this bacterium to become an effective intracellular pathogen but also allowed the bacterium to withstand the effects of macrophage defense mechanisms such as Nramp1 early in the evolution of its pathogenic character [6].

High impact information on Slc11a1

• Bcg affects the capacity of macrophages to destroy ingested intracellular parasites early during infection [7].
• Natural resistance to infection with intracellular parasites is controlled by a dominant gene on mouse chromosome 1, called Bcg, Lsh, or Ity [7].
• Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg [7].
• We have assembled a 400 kb bacteriophage and cosmid contig within the genomic interval containing Bcg [7].
• Lsh, a member of the SNF2 family, is required for genome-wide methylation [8].

Chemical compound and disease context of Slc11a1

• Mice susceptible to infection by various intracellular pathogens including Leishmania donovani and Salmonella typhimurium carry a glycine to aspartic acid substitution at position 169 (G169D, Gly(169)-->Asp), within transmembrane domain 4 of Slc11a1 [3].
• The Bcg alleles of segregating animals were established by in vivo infection with Mycobacterium bovis (Bacillus Calmette-Guérin) strain Montreal. Genomic DNA prepared from progenitor mouse strains was isolated, digested with restriction endonucleases, and analyzed by Southern blotting to identify strain-specific RFLP for each DNA marker tested [9].
• Cytokine-mediated activation of macrophages from Mycobacterium bovis BCG-resistant and -susceptible mice: differential effects of corticosterone on antimycobacterial activity and expression of the Bcg gene (Candidate Nramp) [10].
• The full expression of the ity phenotype in ityr mice requires C3 activation by Salmonella lipopolysaccharide [11].
• MATERIAL: Distinct mouse strains previously described as Bcg susceptible or resistant were inoculated intrathoracically with different doses of live M. bovis BCG [12].

Biological context of Slc11a1

• During macrophage activation, Slc11a1 exerts pleiotropic effects on gene regulation and function, including generation of nitric oxide (NO) via inducible NO synthase (iNOS; encoded by Nos2A) and of reactive oxygen intermediates (ROI) via the phagocyte oxidase complex [13].
• All together, these results are consistent with an impact of Slc11a1 on Th cell differentiation during chronic S. enterica serovar Enteritidis infection [1].
• Kinetics of infection in 129S6 mice and Slc11a1-deficient (129S6-Slc11a1(tm1Mcg)) mice demonstrated that the wild-type allele of Slc11a1 contributed to the S. enterica serovar Enteritidis carrier state as early as 7 days postinfection [1].
• We propose that the G169D mutation causes localized misfolding of Slc11a1, resulting in its retention in the ER and manifestation of the loss of function phenotype [3].
• Correct endosomal targeting of wild-type Slc11a1 continued despite disruption of N-glycosylation sites, indicating that glycosylation did not influence folding or sorting [3].

Anatomical context of Slc11a1

• Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1(+)(/)(+) (Slc11a1(+)(/)(+)) mice despite the presence of high levels of anti-S. typhimurium antibody [14].
• In the present study the role of Slc11a1 in iron turnover is examined in macrophages transfected with Slc11a1(Gly169) (wild-type) or Slc11a1(Asp169) (mutant=functional null) alleles [15].
• Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity [13].
• We found occasional late endosome/lysosome staining of mutant protein using immunoelectron microscopy, but most of the mutant Slc11a1 was retained within the ER (endoplasmic reticulum) [3].
• We used the murine macrophage cell line RAW264.7, stably transfected with functional (RAW-37) or nonfunctional (RAW-21) Nramp1, to study for differences in the expression of NO, a central antimicrobial effector molecule of macrophages [16].

Associations of Slc11a1 with chemical compounds

• Northern blotting analysis indicated that Nramp1 expression was restricted to J774A.1 and RAW 264.7 macrophage lines and was dramatically increased by treatment with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) [5].
• The mitochondrial electron transport inhibitors, rotenone and thenoyltrifluoroacetone, inhibited respiratory burst, and rotenone suppressed L-arginine flux, implying that mitochondrial-derived oxygen radicals are important mediators in Nramp-regulated signal transduction pathways [17].
• The results are discussed in relation to the possible function of the recently cloned candidate gene Nramp, which has structural identity to eukaryote transporters and an N-terminal cytoplasmic proline/serine-rich putative SH3 binding domain [18].
• The N-terminal sequence also carries a proline/serine rich putative SH3 binding domain, consistent with a role for tyrosine kinases in regulating Nramp function [19].
• Nramp1 expression supports increased acute cytoplasmic influx of iron, detected using the fluorescent iron sensor dye calcein [20].

Physical interactions of Slc11a1

• Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype [21].

Co-localisations of Slc11a1

• Gold labelling and electron microscopy defines these compartments more precisely as electron-lucent late endosomal and electron-dense lysosomal compartments, with Nramp1 colocalizing with Lamp1 and cathepsins D and L in both compartments, with macrosialin in late endosomes, and with BSA-5 nm gold in pre-loaded lysosomes [22].

Regulatory relationships of Slc11a1

• Functional gp91phox and iNOS are required to control S. enterica serovar Typhimurium in non-Slc11a1-regulated phases of infection [13].
• Taken together, these results suggest for the first time that Nramp1 controls macrophage SLPI mRNA and protein expression, and can also have an important effect on the kinetics of wound healing [23].
• Ity influences the production of IFN-gamma by murine splenocytes stimulated in vitro with Salmonella typhimurium [24].
• We investigated if c-Myc also regulates Nramp1 expression [25].
• Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism [26].

Other interactions of Slc11a1

• Delayed cutaneous wound healing in mice lacking solute carrier 11a1 (formerly Nramp1): correlation with decreased expression of secretory leukocyte protease inhibitor [23].
• In contrast to the previously described macrophage-specific Nramp gene, Nramp2 mRNAs were found to be expressed at low levels in all tissues tested [27].
• Two of these new marker genes were found very tightly linked to Bcg: Des was located 0.3 +/- 0.3 cM distal from (Vil,Bcg) and 0.3 +/- 0.3 cM proximal to Inha [28].
• In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata [29].
• The presence of a Th2 bias in Slc11a1-deficient mice is associated with improved bacterial clearance [1].

Analytical, diagnostic and therapeutic context of Slc11a1

• A candidate gene expressed in macrophages has been identified by positional cloning and full-length sequence analysis, and encodes the Natural resistance-associated macrophage protein (Nramp) [17].
• In an effort to clone genomic sequences overlapping Bcg, we have used pulsed-field gel electrophoresis (PFGE) and fluorescence in situ hybridization to construct a physical map of the 3.9-Mb segment of proximal mouse chromosome 1, near Bcg [30].
• Detailed restriction mapping of this region identifies numerous putative CpG islands, suggesting that several transcription units are present in the vicinity of Bcg [30].
• In vivo, Nramp1 mRNA expression could be up-regulated in macrophage populations by intraperitoneal injection of either LPS or thioglycollate [31].
• Using lentiviral transgenesis, we generated NOD mice in which Slc11a1 is silenced by RNAi [32].

References