Screening human genome to dissect mechanisms of susceptibility to mycobacterial infection and tuberculosis

With more than 10 million new cases annually, tuberculosis remains a global health problem. Drug-resistant strains of Mycobacterium tuberculosis are spreading and new therapeutic approaches are urgently needed. Host-directed therapies (HDT) target the host rather than the pathogen, aiming to improve immune mechanisms by augmenting the ability of host cells to kill M. tuberculosis or modulating the immune response to prevent excessive inflammation and tissue damage. Progress with HDT development is slowed down by the limited understanding of the host-pathogen interactions during tuberculosis. Whole genome screens can identify human genes involved in responses to mycobacterial infection and suggest potential targets for HTD. I will describe our approach to such human genome screens, covering studies of rare patients with Mendelian susceptibility to mycobacterial infections, genome-wide association studies in cohorts of tuberculosis patients, transcriptome analyses of macrophages infected with mycobacteria and CRISPR-Cas9-mediated screens aiming to dissect macrophage responses to mycobacterial infection.