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

TLDR

In mice, natural resistance or susceptibility to intracellular parasite infection is governed by the Bcg, Lsh, and Ity loci on chromosome 1, which regulate early microbial replication in reticuloendothelial organs. The authors generated Nramp1‑null mice and compared parasite replication profiles, revealing that the Nramp1Asp169 allele is a null allele and underscoring the critical role of this residue in the protein’s mechanism of action. Positional cloning identified Nramp1 as a macrophage‑specific membrane transporter; its targeted disruption eliminates resistance to Mycobacterium bovis, Leishmania donovani, and lethal Salmonella typhimurium, proving that Nramp1, Bcg, Lsh, and Ity are the same locus, while Nramp1‑null mice still clear infection in the late immune phase, indicating Nramp1’s role is confined to early macrophage‑parasite interactions via a cytocidal or cytostatic mechanism distinct from activated macrophages.

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.