Grant: Operating Grant

Tuberculosis is a major threat to global health and disproportionally threatens Canadian marginalized populations. Identification of human genes controlling resistance and susceptibility to tuberculosis is crucial to developing new treatments and vaccines as well as preventing transmission. Tuberculosis is a two phase disease. In the first phase, susceptible human hosts become infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. Infected people are said to suffer from latent tuberculosis infection (LTBI). Importantly, LTBI does not result in any clinical symptoms of disease. In the second phase, LTBI advances to clinical tuberculosis. Both phases are characterized by extensive inter-individual variability of susceptibility. Of the people exposed to M. tuberculosis only a proportion will develop TB, and among LTBI persons less than 10% will advance to clinical disease. Overwhelming evidence supports an important role of host genes in this interindividual variation of susceptibility. We have focused our experiments on the first phase (infection) and we have shown heritability of infection susceptibility in excess of 50%. We have also identified the location of a major locus controlling infection susceptibility on chromosome 11 of the human genome. The present application will focus on the molecular isolation of gene variants that make a person innately resistant to infection with Mycobacterium tuberculosis. To accomplish this task, we will employ cutting edge methods of genetic epidemiology, next generation sequencing and systems genetics analysis of the results. This will result in the identification of human genetic variants that control susceptibility to infection with M. tuberculosis. Innate resistance to infection is the holy grail of tuberculosis research since without infection no tuberculosis disease can develop.