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 129S6 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 129S6 mice and Slc11a1-deficient (129S6-Slc11a1(tm1Mcg)) 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 129S6 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 129S6-Slc11a1(tm1Mcg) mice had higher levels of immunoglobulins earlier in the infection. Quantitative reverse transcription-PCR revealed an increase in Th1 cytokine (Ifng and Il12) and Th1-specific transcription factor Tbx21 expression during infection in both the 129S6 and 129S6-Slc11a1(tm1Mcg) strains. However, the expression of Gata3, a transcription factor involved in Th2 polarization, Cd28, and Il4 was markedly increased in Slc11a1-deficient mice during infection, suggesting a predominant Th2 phenotype in 129S6-Slc11a1(tm1Mcg) animals following S. enterica serovar Enteritidis infection. A strong immunoglobulin G2a response, reflecting Th1 activity, was observed only in 129S6 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.
Caron
Judith
J
Department of Human Genetics, McGill University, Montreal, QC, Canada H3G 1A4.
Larivière
Line
L
Nacache
Mayss
M
Tam
Mifong
M
Stevenson
Mary M
MM
McKerly
Colin
C
Gros
Philippe
P
Malo
Danielle
D
D000818:Animals; D027682:Cation Transport Proteins / Q000502:physiology*; D016764:Cell Polarity; D016207:Cytokines / Q000097:blood; D020869:Gene Expression Profiling; D017578:Immunoglobulin Class Switching; D007964:Leukocytosis / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012477:Salmonella enteritidis; D013154:Spleen / Q000473:pathology; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D014158:Transcription, Genetic; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D016207:Cytokines; D000099173:Natural Resistance-associated Macrophage Protein 1