Molecular genetics of inherited susceptibility to intracellular parasites

In the mouse, innate susceptibility to infection with mycobacteria is controlled by the Bcg host resistance locus. Phenotypically, the locus displays two alleles, a dominant resistance and a recessive susceptibility allele. The cell type expressing the resistance locus is the mature tissue macrophage. We have immortalized macrophages from Bcgr and Bcgs mice and found that macrophage cell lines of Bcgr origin, in comparison to those derived from Bcgs mice have an increased microbicidal activity and show increased expression of a number of molecules known to be associated with macrophage activation. This is in agreement with our earlier finding that Bcgr macrophages are at an advanced stage of macrophage priming for activation. The Bcg gene is located on the proximal region of mouse Chromosome 1. We have obtained a detailed genetic map in the vicinity of Bcg and identified three markers within 1 cM of the resistance locus. These three markers have been used for the generation of a physical map of this area of mouse Chromosome 1 and can be used as anchor points for the cloning of the Bcg host resistance gene. The chromosomal segment in the proximity of the Bcg locus in the mouse is precisely conserved on the telomeric region of the long arm of human Chromosome 2. Investigations of linkage of genetic markers present on human Chromosome 2q with susceptibility to tuberculosis have so far generated a LOD score of + 2.4. Linkage of Chromosome 2q markers with susceptibility to mycobacterial disease supports the existence of susceptibility genes in humans and suggests a human homologue of the mouse Bcg gene as a prime candidate for a human innate susceptibility locus.