Evolutionary history and factors driving the spread of tuberculosis
Mycobacterium tuberculosis is the deadliest bacterial infectious agent globally and the first contributor to antimicrobial mortality. Using comparative genomics and pathophysiological approaches applied to strain lineages with different epidemic and/or antibiotic resistance profiles, we aim at identifying the factors that have contributed to its emergence and its exceptional evolutionary success, including in multidrug-resistant (MDR) forms. This work has led to the discovery of exceptional ancestral branches of tubercle bacilli in East Africa, including a new sister clade of the M. tuberculosis complex (MTBC), as well as outstanding TB clinical isolates with a smooth colony morphotype, named M. canettii, showing mosaic genomes and inter-strain recombination in contrast to the highly clonal structure of the MTBC.  The latter strains that are also less persistent during host infection than M. tuberculosis likely represent an extant reflection of the ancestral, free-living bacterial pool from which the MTBC emerged. With help of Cyril Gaudin (internal collaboration with ERA4TB team), whole genome sequencing (WGS) analysis of M. canettii mutants obtained after experimental evolution revealed that mechanisms conferring increased resistance to host-induced stress were key in the emergence of persistent TB strains. We also used WGS to reveal molecular and historical factors that favored the emergence and the longitudinal spread of major epidemic multi-drug resistant clones, member of the major Beijing/L2 lineage of the MTBC. The extensive resistance and the outstanding genetic arsenal of these geographically widespread MDR strains represent a “perfect storm” that jeopardizes the successful introduction of new anti-MDR-TB antibiotic regimens. With the CRyPTIC consortium, genetic determinants of drug resistance are further comprehensively catalogued across the genomes of globally circulating M. tuberculosis strains. The development and international deployment with GenoScreen of the innovative next generation sequencing-based diagnostics Deeplex Myc-TB, which has a uniquely extended diagnostic spectrum (see Translational Research), represents a new powerful tool to combat the spread of such highly resistant clones.