Genetic control of susceptibility to tuberculosis in resistant C57BL/6 (B6) and susceptible DBA/2 (D2) mice is multigenic. Susceptibility in D2 is associated with a unique phenotype which includes unrestricted pulmonary replication, severe lung pathology, extensive tissue necrosis and early death. Quantitative trait linkage mapping in 2 genome wide scans was used to determine the number and location of genes controlling differential susceptibility to pulmonary tuberculosis in D2 and B6. In a first scan, 95 informative (B6XD2) F2 mice were infected i.v with 105 virulent M. tuberculosis H37Rv, and survival time was used as a phenotypic measure of susceptibility. These studies identified 3 significant linkages on chromosomes 1,3 and 7 designated Trl-1/2/3 respectively. In a second genome scan, 104 (B6XD2) F2 mice were infected with 10 2 M. tuberculosis H37Rv by the aerosol route, and the extent of bacterial replication in the lungs (CFU) at 90 days was used as a phenotypic measure of susceptibility. Results from this analysis identified a major linkage on chromosome 19 (Trl-4) accounting for 25% of the phenotypic variance. In this scan Trl-3 was confirmed as not only playing a role in overall survival to infection but also bacterial growth in the lungs. Our results suggest a strong genetic interaction between Trl-3 and Trl-4 in regulating pulmonary replication of M. tuberculosis. To further characterize the mechanistic basis of action of the Trl-1/2/3/4 effect on M. tuberculosis infection, global expression analysis of approximately 15 250 genes was utilized to identify genes differentially expressed between the lungs of B6 and D2 mice prior to and during infection with M. tuberculosis . Our data suggests that the classical complement pathway and the apoptotic pathway plays a role in the differential susceptibility between B6 and D2 mice, with these pathways being upregulated in B6. Moreover the increase in neutrophil associated gene expression corroborates with our histological finding of increased neutrophil cell counts in D2 mice. Finally these studies have provided candidate genes that map in the Trl-1 and Trl-4 regions (Cfh and Scd2 respectively).
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.100657 |
| Date | January 2005 |
| Creators | Mitsos, Louika-Maria. |
| 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 Biochemistry.) |
| Rights | © Louika-Maria Mitsos, 2005 |
| Relation | alephsysno: 002326496, proquestno: AAINR25211, Theses scanned by UMI/ProQuest. |
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