title: Functional validation of the genetic architecture of Salmonella Enteritidis persistence in 129S6 mice.
abstract: The Gram-negative bacteria, Salmonella, cause a broad spectrum of clinical diseases in humans, ranging from asymptomatic carriage to life-threatening sepsis. We have designed an experimental model to study the contribution of genetic factors to the persistence of Salmonella Enteritidis during the late phase of infection in 129S6/SvEvTac and C57BL/6J mice. C57BL/6J mice cleared the bacteria from their reticuloendothelial system within a period of 42 days, whereas the 129S6 mice still presented a high bacterial load. Using this model, we have identified ten Salmonella Enteritidis susceptibility loci (Ses1, Ses1.1, and Ses3-Ses10) associated with bacterial persistence in target organs of 129S6/SvEvTac mice using a two-locus epistasis QTL linkage mapping approach. Significant statistical interactions were detected between Ses1 on chromosome 1 and Ses5 on chromosome 7 and between Ses1 and Ses4 on chromosome X. In this study, we functionally validated the genetic architecture of Salmonella persistence in 129S6 mice using single- (129S6.B6-Ses1.2 that combines Ses1 and Ses1.1 loci, 129S6.B6-Ses4, and 129S6.B6-Ses5) and double-congenic mice (129S6.B6-Ses1.2/Ses4 and 129S6.B6-Ses1.2/Ses5). These experiments demonstrate functional interactions between Ses1.2 and Ses4 or Ses5 that improve Salmonella Enteritidis clearance, validating the critical role played by gene-gene interactions in the contribution to bacterial clearance heritability. Improved bacterial clearance in double-congenic mice could be explained by the impact of Ses4 and Ses5 in combination with Ses1.2 on TH polarization since a TH2 bias (decreased Ifng and increased Il4 mRNA levels and reduced IgG2a immunoglobulins in the serum) was observed in 129S6.B6-Ses1.2/Ses5 mice and a TH17 (high Il17 expression) bias in 129S6.B6-Ses1.2/Ses4.
authors.affiliation: Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Chevenon
authors.forename: Mayss
authors.initials: M
authors.lastname: Naccache
authors.forename: Megan M
authors.initials: MM
authors.lastname: Eva
authors.forename: Rabia T
authors.initials: RT
authors.lastname: Khan
authors.forename: Danielle
authors.initials: D
authors.lastname: Malo
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice / Q000235:genetics*; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D012480:Salmonella Infections / Q000235:genetics* / Q000382:microbiology*; D012477:Salmonella enteritidis / Q000502:physiology*