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

Natural resistance to infection with intracellular parasites is contro lled by a dominant gene on mouse chromosome 1, called Bcg, Lsh, or Ity . Bcg affects the capacity of macrophages to destroy ingested intracel lular parasites early during infection. We have assembled a 400 kb bac teriophage and cosmid contig within the genomic interval containing Bc g. A search for transcription units by exon amplification identified s ix novel genes in this contig. RNA expression studies showed that one of them, designated Nramp, was expressed exclusively in macrophage pop ulations from reticuloendothelial organs and in the macrophage line J7 74A. Nramp encodes an integral membrane protein that has structural ho mology with known prokaryotic and eukaryotic transport systems, sugges ting a macrophage-specific membrane transport function. Susceptibility to infection (Bcg(s)) in 13 Bcg(r) and Bcg(s) strains tested is assoc iated with a nonconservative Gly-105 to Asp-105 substitution within pr edicted transmembrane domain 2 of Nramp.