Genetic and functional mechanisms of susceptibility to mycobacterial infection.

To find genetic variants associated with TB we now undertake a genome-wide association study in 6,000 HIV-negative pulmonary TB patients and 6,000 healthy controls from Russia. Here we propose to identify causative variants in the associated regions using fine-mapping experiments in the Russian TB sample collection and studies in the TB case-control collections from other populations. We will undertake genetic analysis of the host pathogen interaction using information about genetic variation in 2,600 M. tuberculosis isolates collected from the same Russian TB patients. We will use in vitro model of M. tuberculosis infection in the primary immune cells from 1,000 healthy volunteers to study their permissiveness to mycobacteria and to find transcripts that are differentially regulated in the immune cells upon infection. We will combine these data with the genome-wide analysis of variation in the same subjects to discover DNA polymorphisms that control differential regulation gene expres sion upon mycobacterial infection and explain inter-individual variability. Finally, we will sequence exomes of patients with severe TB to find causative mutations and will validate their biological role in the following functional experiments.