Resistance to salmonellosis in the chicken is linked to NRAMP1 and TNC

Natural resistance to infection with Salmonella typhimurium in mice is controlled by two major loci, Bcg and Lps, located on mouse chromosomes 1 and 4, respectively. Both Bcg and Lps exert pleiotropic effects and contribute to cytostatic/cytocidal activities of the macrophage. Bcg encodes for a membrane phosphoglycoprotein designated Nramp1 (natural resistance-associated macrophage protein 1), which belongs to an ancient family of membrane proteins. Lps has not been cloned yet, but its location on mouse chromosome 4 has been refined for positional cloning. As in mice, chicken inbred lines differ in their susceptibility to infection with Salmonella typhimurium. We have tested the candidacy of the chicken homologs of Nramp1 and Tnc (a locus closely linked to Lps), in the differential resistance of chicken inbred lines to infection with S. typhimurium. We have first analyzed six inbred chicken lines of Salmonella-resistant or Salmonella-susceptible phenotypes for the presence of nucleotide sequence variations within the coding portion of NRAMP1. We have identified 11 sequence variations within NRAMP1 in the chicken inbred lines tested: 10 of these represented either silent mutations or conservative changes. However, one G --> A substitution at nucleotide 696 resulted in the nonconservative replacement of Arg(223) to Gln(223) within the predicted TM5-6 region. This allelic variant was specific to the susceptible line C and not observed in any of the resistant strains. To investigate the effect of NRAMP1 and TNC on resistance to infection with S. typhimurium, 425 (W1 x C)F-1 x C chicken progeny were examined during a period of 15 days postinfection. Together, NRAMP1 and TNC explain 33% of the early differential resistance to infection with S. typhimurium of parental lines C and W1. Our data established that resistance to infection with S. typhimurium in chickens is inherited as a complex trait and that comparative mapping has proven to be useful to identify Salmonella-resistance genes in the chicken.