International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Mitsos L M
Dept of Biochemistry & Center for Host Resistance, McGill University

Co-Authors: 2) Nantel A, 3) Cardon L R, 4) Ryan L, 4) LaCourse R, 4) North R J, 1) Gros P.
Institutions: 1) Dept of Biochemistry & Center for Host Resistance, McGill University, 2) Biotechnology Research Institute, National Research Council, 3) Bioinformatics and Statistical Genetics, University of Oxford, 4) Trudeau institute

The mouse DBA/2 strain is very susceptible to infection with virulent Mycobacterium tuberculosis, while C57BL/6 is much more resistant. This DBA/2 susceptibility includes unrestricted pulmonary microbial replication, massive inflammatory response, and early death. To identify the genes regulating growth of M. tuberculosis in the lungs of these two strains, 98 informative (C57BL/6 X DBA/2) F2 mice were infected by the respiratory route with M. tuberculosis H37Rv (200 CFU), and the extent of bacterial replication in the lungs at 90 days was used as a quantitative measure of susceptibility in a whole genome scan. QTL mapping identified a major locus on chromosome 19 (Trl-4; LOD 5.6) which regulated pulmonary replication of M. tuberculosis and accounted for 25% of the phenotypic variance. An additional effect of a locus (Trl-3), previously shown to affect survival to i.v. infection with M. tuberculosis, was also noted. F2 mice homozygous for C57BL/6 alleles at both Trl-3 and Trl-4 were as resistant as C57BL/6 parents, while mice homozygous for DBA/2 alleles were as susceptible as DBA/2 parents. These results suggest a strong genetic interaction between Trl-3 and Trl-4 in regulating pulmonary replication of M. tuberculosis.

Mouse lines doubly congenic for Trl-3 and Trl-4 are being generated and will be used in transcriptional profiling experiments to establish a compendium of genes differentially expressed in normal and in M. tuberculosis infected tissues from these mouse strains. This list will be related to the transcript map of the Trl-3/4 regions to suggest positional candidates for the noted gene effects.

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