The contribution of host genetics to tuberculosis pathogenesis.

Assessment of the contribution of host genetics to human tuberculosis is a long-standing research challenge. Evidence of genetic factors has come primarily from twin studies and risks to first-degree relatives of cases. In addition, inferences of strong genetic influences have come from anecdotal accounts of socially prominent families, population variation in TB incidence and susceptibility to infection, and secular changes in TB severity, incidence and mortality inferred from historical information of contact between different populations, as well as accidental inoculation of vaccinees with M.tuberculosis. Recently, a major tuberculosis susceptibility locus has been mapped to the long arm of human chromosome. A number of host genetic factors have been directly implicated in tuberculosis susceptibility but strong genetic effects on tuberculosis risk have been difficult to detect both by candidate gene and genome-wide association studies. The reason for our current inability to trace strong genetic effects is unknown. However, a number of possible explanations are supported by direct experimental data. For example, it has been shown that host genetic control of susceptibility is limited to specific host M.tuberculosis strain combinations. In addition, it is known that proper inclusion of gene environment interactions is of critical importance for the detection of strong host genetic effects on tuberculosis susceptibility. By contrast, few genetic studies stratify on M.tuberculosis or try to model gene-environment interactions. Until now, most of the human genetics studies in tuberculosis have focused on the identification of genetic variants that impact on progression from infection to disease. There are few studies that aim at the identification of genes that impact on resistance to infection with M.tuberculosis or genes that control the extent of anti- mycobacterial immunity. Yet, estimates of heritability for these quantitative traits provide clear evidence for an important role of host genetics in anti-mycobacterial immunity. Recent work involving scientists from South Africa, France and Canada has focused on the study of innate resistance to infection with M. tuberculosis. Employing the tuberculin skin test as a tool to evaluate resistance to infection, a major locus (TST1) on chromosomal region 11p14 was identified that T-cell independent resistance to M. tuberculosis. In addition, a second major locus (TST2), on chromosomal region 5p15 was identified that controls the intensity of T-cell mediated delayed type hypersensitivity (DTH) to tuberculin. These results pave the way for the understanding of the molecular mechanisms involved in resistance to M. tuberculosis infection in endemic areas (TST1), and for the identification of critical regulators of T-cell dependent DTH to tuberculin (TST2). The finding of a strong host genetic control of anti-mycobacterial immunity raises the questions to what extent host genetics will be a barrier to the development of a universally efficacious tuberculosis vaccine. In fact, epidemiological studies in highly endemic areas and experiments in animal models suggest a strong contribution of host genetic factors to vaccine efficacy making the identification of the corresponding genes one of the new frontiers of mycobacterial research.