Grant: CIHR Fellowship

Tuberculosis (TB) is an infectious human disease caused by Mycobacterium tuberculosis which results in more than two million deaths each year. Transmission of TB occurs by aerosol from infectious patients to unaffected persons. However, only a proportion of those exposed to M. tuberculosis will become infected with the tubercle bacillus. Of those who are infected, less than 10% will go on and develop clinical TB disease over their life time. People who are infected with M. tuberculosis and who show no symptoms are said to have latent TB infection. One hundred years of studies have assembled strong evidence that progression from exposure to infection and from infection to clinical TB disease are under strong host genetic control. In my project, I will study the genetic control of the transition from exposure to infection. My main hypothesis is that human resistance to latent TB infection is due (i) to a collection of rare mutations (<5% frequency) with strong biological effects, and (ii) to subtle, genetically controlled fluctuations of biological activity in the pathways used by the human host to fight off the invading tubercle bacillus. To test my hypothesis, I will have access to a unique resource of biological samples from Cape Town, an area with one of the globally highest rates of TB. In addition, I will have access to the latest genome technologies via the Genome Quebec and McGill University Innovation Centre and to the high performance computing clusters of Compute Canada. My project is, however, fundamentally distinct from previous studies of host genetics of infectious disease. My major goal is to integrate the findings that I will make into a higher level of systems genetics. I expect that genetic variation associated with very modest effect size when considered alone will reveal its true importance for maintaining cellular homeostasis and fighting off invading pathogens once analysed in the context of higher order cellular pathways.