Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines

Abstract

Two lines of mice selected to produce maximal (AIRmax) or minimal (AIRmin) acute inflammatory reactions (AIR) differ in their susceptibility to infection by Salmonella enterica serotype Typhimurium ( S. Typhimurium). The LD 50 for AIRmax mice is 1000 times higher than that observed for AIRmin mice, and higher frequencies of Slc11a1 alleles (known to confer either resistance ( R) or high susceptibility ( S) to S. Typhimurium) were consistently found in AIRmax and AIRmin mouse lines, respectively. In order to evaluate the effect of the quantitative trait loci (QTL) segregated in AIRmax and AIRmin mice on Slc11a1 dependent susceptibility to S. Typhimurium, the R and S alleles were fixed in homozygosity in AIRmax and AIRmin backgrounds by genotype assisted breedings. These new lines were named AIRmax RR , AIRmax SS , AIRmin RR , and AIRmin SS . Acute inflammation of Slc11a1 RR animals was more severe in comparison to their Slc11a1 SS counterparts, implicating Slc11a1 (or other linked genes) in AIR regulation. The LD 50 of S. Typhimurium was 800-times higher for AIRmax SS than for AIRmin SS , demonstrating that AIR QTL can act as modifiers of the Slc11a1 SS susceptibility gene. Four microsatellite markers for S. Typhimurium susceptibility QTL described in other mouse lines showed specific allele fixation in AIRmax or AIRmin mice, suggesting that these chromosomal regions also segregate with inflammatory phenotypes.