Salmonella infections remain a global health concern exacerbated by the emergence of multidrug resistant strains. Host genetics have been demonstrated to influence the immune response to Salmonella infections. Adopting the susceptible wild-derived MOLF/Ei mice as a model of systemic Salmonella Typhimurium infection has previously identified a resistance locus Ity2 and a susceptibility locus Ity3. / Both the Ity2 and Ity3 loci were validated through the creation of congenic mice and through linkage confirmation in a new segregating cross. Refinement of the critical intervals was achieved using subcongenic mice. Transcriptional profiling of the congenic mice identified differentially regulated candidate genes within the two loci that can be examined for potential relevance to Salmonella infection in MOLF/Ei mice. / Previous studies proposed Tlr5 as a candidate for Ity3 based on the sequence variants and reduced expression in MOLF/Ei liver. Tlr5 function was characterized in vitro and in vivo using the Ity3 congenic strains. Both analyses pointed towards the exclusion of this gene as a candidate for Ity3 due to discordant functional responses between MOLF/Ei and the Ity3 congenics. / Ncf2 was pursued as a candidate for the Ity3 locus based on its map position and its antimicrobial role in Salmonella infection. Sequencing of Ncf2 led to the identification of one non-conservative amino acid in a conserved domain of the protein. Functional analysis indicated a reduced response attributed to the MOLF/Ei allele, suggesting a potential involvement of Ncf2 in Salmonella pathogenesis of Ity3 congenic mice. / Taken together, we have been able to narrow down the critical intervals and confirm the contribution of Ity2 and Ity3 to Salmonella infection. We have eliminated Tlr5 but highlighted the potential involvement of Ncf2 for the Ity3 locus. The genetic dissection of the host response in MOLF/Ei mice has captured the inherent complexity of the immune response towards Salmonella infection. Our findings have also revealed the genetic and phenotypic diversity of the wild-derived MOLF/Ei mice. Furthermore, a complete genome scan of the additional informative cross as well as the validation of candidates identified here, should resolve of the intricacies of the susceptibility of MOLF/Ei mice and contribute to our understanding of Salmonella pathogenesis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111866 |
| Date | January 2006 |
| Creators | Sancho Shimizu, Maria Vanessa. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002585445, proquestno: AAINR32381, Theses scanned by UMI/ProQuest. |
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