Influence of Slc11a1 on the outcome of Salmonella enterica serovar enteritidis infection in mice is associated with Th polarization

Genetic analyses identified Ses1 as a significant quantitative trait locus influencing the carrier state of 12956 mice following a sublethal challenge with Salmonella enterica serovar Enteritidis. Previous studies have determined that Slc11a1 was an excellent candidate gene for Ses1. Kinetics of infection in 12956 mice and Slc11a1-deficient (12956-Slc11a1(tmIMcg)) mice demonstrated that the wild-type allele of Slc11a1 contributed to the S. enterica serovar Enteritidis carrier state as early as 7 days postinfection. Gene expression profiling demonstrated that 12956 mice had a significant up-regulation of proinflammatory genes associated with macrophage activation at day 10 postinfection, followed by a gradual increase in immunoglobulin transcripts, whereas 12956-Slc11a1(tmIMcg) mice had higher levels of immunoglobulins earlier in the infection. Quantitative reverse transcription-PCR revealed an increase in Th1 cytokine (Ifng and IlI2) and Th1-specific transcription factor Tbx2I expression during infection in both the 12956 and 12956-Slc11a1(tmIMcg) strains. However, the expression of Gata3, a transcription factor involved in Th2 polarization, Cd28, and 114 was markedly increased in Slc11a1-deficient mice during infection, suggesting a predominant Th2 phenotype in 12956-Slc11a1(tmIMcg) animals following S. enterica serovar Enteritidis infection. A strong immunoglobulin G2a response, reflecting Th1 activity, was observed only in 12956 mice. All together, these results are consistent with an impact of Slc11a1 on Th cell differentiation during chronic S. enterica serovar Enteritidis infection. The presence of a Th2 bias in Slc11a1-deficient mice is associated with improved bacterial clearance.