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

Abstract

SummaryIn 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 Beg, Nrampl, which codes for a novel macrophage-specific membrane transport protein. We have created a mouse mutant bearing a null allele at Nrampl, and we have analyzed the effect of such a mutation on natural resistance to infection. Targeted disruption of Nrampl has pleiotropic effects on natural resistance to infection with intracellular parasites, as it eliminated resistance to Mycobacterium boris, Leishmania donovani, and lethal Salmonella typhimurium infection, establishing that Nrampl, Bcg, Lsh, and It), are the same locus. Comparing the profiles of parasite replication in control and Nrampl -/-mice indicated that the NramplAse 169 allele of Beg s 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, Nrampl -/-mutants can overcome the infection in the late immune phase, suggesting that Nrampl 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.

Genetic regulation of host responses to Salmonella infection in mice

“…57 The identity of Nramp1, Bcg, Ity and Lsh was confirmed by targeted disruption of Nramp1 in mice and phenotypic comparison among different genotypes of mice during experimental infections with Salmonella Typhimurium, M. bovis and L. donovani. 46 Additionally, susceptible mice were rendered resistant to BCG and Salmonella Typhimurium by transfer of the resistance allele, further confirming the identity of Nramp1 with the phenotypic resistance to Salmonella Typhimurium. 58 The identification of Nramp1 and its function opens a whole new field in the area of host resistance to intracellular pathogens.…”

“…The identification of a unique gene underlying Ity/ Bcg/Lsh came almost 20 years after its first description. 45,46 Two allelic forms were recognized for Ity: a resistance allele (Ity r ) and a susceptibility allele (Ity s ). 40 The resistance allele is dominant and influences the rate of bacterial growth during the exponential phase of multiplication in the RES and the LD 50 after lethal challenge with high doses of Salmonella Typhimurium.…”

Ramp-ing up allergies: Nramp1 (Slc11a1), macrophages and the hygiene hypothesis

“…As the ability to mount a response to infectious agents is highly heritable, a genetic contribution to the inverse relationship between mycobacterial infection and the development of allergy and asthma is very plausible. In mice, resistance to intracellular bacteria, such as mycobacteria, is under the control of the gene naturalresistance-associated macrophage protein 1 (Nramp1, recently designated Slc11a1) [16]. In humans, there is also an association or linkage of NRAMP1 with susceptibility to infectious diseases [17].…”

Refinement of the genetics of the host response to Salmonella infection in MOLF/Ei: regulation of type 1 IFN and TRP3 pathways by Ity2

“…3 Several mouse strains (C57BL/6J, C3H/HeJ, AcB61 and ITY9) are unable to control bacterial replication and succumb early during the infection. [4][5][6][7] Other strains of mice, such as several 129 substrains, are capable of controlling early bacterial replication and survive the infection. 4,8 The wild-derived MOLF/Ei mice are highly susceptible to infection despite the fact that they are capable of controlling bacterial replication in the target organs.…”