NATURAL-RESISTANCE TO INFECTION WITH INTRACELLULAR PARASITES - ISOLATION OF A CANDIDATE FOR BCG

Natural resistance to infection with intracellular parasites is controlled by a dominant gene on mouse chromosome 1, called Bcg, Lsh, or Ity. Bcg affects the capacity of macrophages to destroy ingested intracellular parasites early during infection. We have assembled a 400 kb bacteriophage and cosmid contig within the genomic interval containing Bcg. A search for transcription units by exon amplification identified six novel genes in this contig. RNA expression studies showed that one of them, designated Nramp, was expressed exclusively in macrophage populations from reticuloendothelial organs and in the macrophage line J774A. Nramp encodes an integral membrane protein that has structural homology with known prokaryotic and eukaryotic transport systems, suggesting a macrophage-specific membrane transport function. Susceptibility to infection (Bcg(s)) in 13 Bcg(r) and Bcg(s) strains tested is associated with a nonconservative Gly-105 to Asp-105 substitution within predicted transmembrane domain 2 of Nramp.