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.
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.
Caron
J
J
Department of Human Genetics, McGill University, Montreal, Canada.
Loredo-Osti
J C
JC
Laroche
L
L
Skamene
E
E
Morgan
K
K
Malo
D
D
D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000502:physiology; D002874:Chromosome Mapping; D002908:Chronic Disease; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D018895:Microsatellite Repeats; D040641:Quantitative Trait Loci; D012480:Salmonella Infections / Q000235:genetics*; D012481:Salmonella Infections, Animal / Q000235:genetics*; D012477:Salmonella enteritidis; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D000099173:Natural Resistance-associated Macrophage Protein 1