Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

Abstract

Genetic factors play a key role in host response, disease severity, and ultimate outcome of infection with Mycobacterium tuberculosis in humans. In the mouse, the DBA/2J strain is very susceptible to M. tuberculosis H37Rv infection, while the C57Bl/6J strain is resistant. In DBA/2J, a heavier bacterial burden causes a unique phenotype, that includes very severe and rapidly fatal pulmonary disease with extensive exudation of neutrophils and tissue necrosis, as opposed to slower progressive pulmonary disease characterized by the accumulation of epithelioid macrophages with protective immune and inflammatory responses in C57Bl/6J. To identify the genes responsible for differences in host response to M. tuberculosis in these two strains, 95 animals of an informative (C57Bl/6J × DBA/2J) F2 cross were infected intravenously with M. tuberculosis (1 × 10⁵ CFU) and duration of survival was used as a quantitative phenotypic measure of susceptibility in a whole genome scan. Quantitative trait locus analysis (QTL) showed that the genetically controlled susceptibility was multigenic. QTL analysis identified two significant linkages on the distal portion of chromosome 1 (Trl-1, LOD, 4.80) and on the proximal portion of chromosome 7 (Trl-3, LOD, 4.66) that each account for approximately 21% of the phenotypic variance. A third suggestive linkage was identified on the proximal portion of chromosome 3 (Trl-2, LOD, 3.93; additional 18% of the variance). At each locus, homozygosity for the parental C57Bl/6J alleles was associated with increased resistance to infection. These novel mouse loci provide the basis for evaluating a possible association of the corresponding syntenic chromosomal regions in humans with susceptibility to tuberculosis.