Salmonella cause a broad spectrum of diseases in humans ranging from asymptomatic carriage to life-threatening sepsis. The disease outcome depends partly on the host genetic background. / The contribution of genes controlling the late phase of a Salmonella infection was studied using a model based on the inoculation of a sublethal dose of S. Enteritidis in 129S6 and C57BL/6J mice. C57BL/6J mice were able to eliminate completely S. Enteritidis from their RES, whereas 129S6 mice could not. Linkage analysis of 302 (C57BL/6J X 129S6) F2 progeny identified three QTLs, Ses1, Ses2, and Ses3. They were associated with disease susceptibility in 129S6 mice, and their estimated effects on bacterial clearance were greater in females. A statistical interaction was detected between Ses1 and Ses2. The model included the QTLs, the interaction and sex as a covariate, and explained 32% of the phenotypic variance suggesting that unidentified modifiers contributed to the phenotype. / A two-locus epistasis QTL linkage analysis conducted separately in the F2 females and males identified additional QTLs with individual effects and epistasic QTLs associated with the Salmonella carrier state of 129S6 mice. The model for females included Ses3 and two significant interactions (Ses1-D7Mit267 and Ses1-DXMit48 ) accounting for 47% of the total phenotypic variance. The model for males included Ses1.1, three interactions (Ses1-D9Mit218, D2Mit197-D4Mit2 and D3Mit256-D13Mit36) and explained 47% of the phenotypic variance. / We constructed congenic mice carrying the Ses1.1, Ses1, Ses2 and Ses3 regions to validate their existence in vivo and to study their impact on Salmonella clearance (129.136). Double congenic mice Ses1/Ses2 were constructed to test functionally the statistical interaction between these QTLs. Phenotypic analysis confirmed that Ses1 and Ses1.1 contribute to bacterial clearance. / The candidacy of Nramp1 as the gene underlying Ses1 was evaluated using Nramp1-deficient mice. 129S6-Nramp1tm1Mcg mice have a significantly lower bacterial load compared to 129S6 mice, suggesting that Nramp1 influences the S. Enteritidis clearance during the late phase of infection. We observed that the 129S6 mice mounted an early and strong TH1 response, whereas the 129S6-Nramp1 tm1Mcg mice mounted an earlier and more vigorous TH 2 response that seems to improve the late phase Salmonella clearance.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85895 |
| Date | January 2005 |
| Creators | Caron, Judith, 1973- |
| 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: 002260883, proquestno: AAINR21632, Theses scanned by UMI/ProQuest. |
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