"Tuberculosis (TB) is not only an infectious disease, as only a small fraction of individuals infected with Mycobacterium tuberculosis (Mtb) develop disease. Over the last century, evidence has accumulated indicating that TB is also a genetic disease. However, the molecular basis of predisposition to TB remains elusive, and efforts to understand the pathogenesis of TB are of prime importance if we are to combat this major killer of mankind. The PI proposes an integrated and innovative research program aiming to identify the genetic variants controlling the critical steps of the process from exposure to Mtb to development of TB. In addition to investigating the two key clinical phenotypes - the development of disseminated TB in children and of pulmonary TB in adults - this program proposes to undertake the first comprehensive genetic dissection of resistance to Mtb infection. Making use of the latest conceptual and technical breakthroughs in human genetics, the strategy will combine Mendelian and complex genetics approaches, including genome-wide (GW) investigations (GW linkage and association studies, whole-exome sequencing). The strengths of this innovative, ground-breaking project lie in its bold hypothesis, the high quality of our clinical samples, and the extensive experience of our laboratory in human genetics of mycobacterial infections in terms of genetic epidemiology, molecular genetics, and immunology. The identification of the main variants controlling TB development will have major implications for TB control, both in the definition of new prevention strategies (design of vaccine research and clinical trials) and in the development of new treatments (aiming to restore deficient immune responses). These findings will also shift paradigms in both human genetics and infectious diseases, as - genetic TB - could provide proof-of-principle for a genetic theory of common infectious diseases."