INTRACELLTB · A Chemical Genomics Approach of Intracellular Mycobacterium tuberculosis Towards Defining Specific Host Pathogen Interactions

Tuberculosis, caused by Mycobacterium tuberculosis is still a major threat to global health. Because the treatment of an infected individual requires more than six months of chemotherapy, compliance is low, which can result in the development of multidrug resistant (MDR-TB) strains. New drugs and new targets are needed to combat MDR-TB. A critical feature of the Mycobacterium tuberculosis bacillus is its ability to survive and even replicate within macrophages, making these host cells an ideal niche for persisting microbes. The goal of our project is to understand the biological mechanisms underlying the persistence of intracellular mycobacteria and to develop novel approaches to eradicate the bacillus from its hiding spot. To this end, we have been undertaking global approaches using visual phenotypic assays (relying on monitoring by automated confocal fluorescence microscopy) of the trafficking and replication of M. tuberculosis inside macrophages. Screening of a small interfering RNA library, a M. tuberculosis transposon mutant library and hundreds of thousands of small chemical molecules has led to the identification of key host and mycobacterial genes involved in the intracellular fate of M. tuberculosis, as well as chemicals able to prevent intracellular bacterial growth. Building on the considerable data generated and on the powerful high throughput / high content (HT/HC) confocal microscopy, our project is to further explore the signalling pathways used specifically by M. tuberculosis. We will focus on the in depth study of bacterial protein effectors belonging to the ESX and PPE families and of the SOCS family member CISH, which promotes intracellular mycobacterial survival. Finally, chemicals that target cellular partners of M. tuberculosis will constitute a new starting point for the development of drugs able to counteract this host response manipulation without directly targeting the pathogen, thereby overcoming the issue of the emergence of MDR-TB.