Resistance and susceptibility to tuberculosis analysed at the transcriptome level: lessons from mouse macrophages

Gene expression patterns associated with resistance and susceptibility to tuberculosis (TB) were investigated at the macrophage level in the well-defined mouse model of infection. Oligonucleotide microarrays were used to analyse the regulation of gene expression in murine bone marrow-derived macrophages infected with Mycobacterium tuberculosis. Four mouse strains, known to differ in terms of growth permissiveness for M. tuberculosis in infected tissues, in the development of pulmonary pathology, and in the rate of premature death due to tuberculosis, were compared: C57BL/6 and BALB/c representing resistant, DBA/2 and CBA/J representing susceptible mouse strains. Genes (55) were regulated more than two-fold in macrophages of all strains investigated following M. tuberculosis infection. Importantly, 18 genes were commonly regulated only in macrophages of the two resistant strains upon infection, and 102 genes were commonly regulated exclusively in macrophages of the two susceptible strains. Using this approach, we have therefore identified more than 100 genes potentially associated with resistance and susceptibility, respectively, to TB at the macrophage level. A tentative interpretation of our microarray data suggests that macrophages from susceptible mice predominantly stimulate the recruitment of cells that contribute disproportionately to tissue damage rather than to microbial elimination. In conclusion, microarray gene chips are useful tools for generating new hypotheses about resistance and susceptibility to TB, and the mouse model can now be used to subject candidate genes identified by this approach to further functional analyses.