Identification of Genetic Loci Controlling Bacterial Clearance in Experimental Salmonella Enteritidis Infection: An Unexpected Role of Nramp1 (Slc11a1) in the Persistence of Infection in Mice

Genes Immun. 2002 Jun;3(4):196-204. doi: 10.1038/sj.gene.6363850.

Abstract

The Gram-negative bacteria, Salmonella, cause a broad spectrum of clinical diseases in both animals and humans ranging from asymptomatic carriage to life-threatening sepsis. We have developed a model to study the contribution of genetic factors to the susceptibility of 129sv and C57BL/6J inbred mice to Salmonella enteritidis during the late phase of infection. C57BL/6J mice were able to eliminate completely sublethal inoculums of S. enteritidis from their reticuloendothelial system, whereas 129sv mice could not even after 60 days post inoculation. A genome scan performed on 302 (C57BL/6J x 129sv) F2 progeny identified three dominant loci (designated Ses1 to Ses3) that are associated with disease susceptibility in 129sv mice. Two highly significant linkages were identified on chromosomes 1 (Ses1) and 7 (Ses2) with respective LOD scores of 9.9 (P = 1.4 x 10(-11)) at D1Mcg5 and 4.0 (P = 1.9 x 10(-5)) at D7Mit62. One highly suggestive QTL was located on chromosomes15 (Ses3) with a LOD score 3.4 (P = 1.2 x 10(-4)). The estimated effects of Ses1, Ses2 and Ses3 on the bacterial clearance were greater in females. Using a model of three loci, with interaction between Ses1 and Ses2 and sex as a covariate, the three QTLs explained 32% of the phenotypic variance. The candidacy of Nramp1 as the gene for Ses1 was evaluated using mice carrying a null allele at Nramp1 (129sv-Nramp1(tm1Mcg)). These mice have a significantly lower spleen bacterial load compared to the wild-type 129sv mice, strongly suggesting the involvement of Nramp1 in controlling S. enteritidis clearance during the late phase of infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / physiology
  • Chromosome Mapping
  • Chronic Disease
  • Crosses, Genetic
  • Disease Models, Animal
  • Female
  • Lod Score
  • Mice
  • Mice, Inbred C57BL
  • Microsatellite Repeats
  • Quantitative Trait Loci
  • Salmonella Infections / genetics*
  • Salmonella Infections, Animal / genetics*
  • Salmonella enteritidis*

Substances

  • Cation Transport Proteins
  • natural resistance-associated macrophage protein 1