<i>In Host</i> Mutational Adaptation of <i>Mycobacterium Tuberculosis</i> Complex Strains During Tuberculosis Infection

BACKGROUND: Tuberculosis (TB) is the leading cause of death from an infectious disease worldwide. Mutations arising in Mycobacterium tuberculosis complex (MTBC) strains during TB infection provide a record of bacterial adaptations, such as those needed to survive the attack of the immune system and antibiotic therapies. METHODS: We conducted a meta-analysis of MTBC sequenced strains with multiple isolates from the same patient, sourced from published studies and TB Portals. We applied a convergent evolution approach to identify heavily mutated MTBC loci across patients and estimated the rates of drug resistance (DR) acquisition during treatment. RESULTS: Using 5882 high-quality genomes from 1044 patients with TB, we identified 21 genes, 25 operons, and 27 promoter regions statistically enriched by mutations compared with the rest of the genome, and additional loci with established and plausible adaptive roles approaching statistical significance. Significantly, these included multiple loci known to be involved in resistance to first-, second-, and last-line anti-TB drugs. Previously reported candidate drug-resistance and -tolerance genes (prpR, Rv2571c, fadD11, helY, ndhA, Rv0139, fadE5, bioF2, and mce1 operon) were also identified. Genes encoding regulators (phoR, whiB6, and mycP1) and effectors (espK and eccE1) of the virulence ESX-1 locus were frequently mutated in host. Fluoroquinolone resistance was acquired more frequently during treatment than resistance to any other anti-TB drug. CONCLUSIONS: We show that frequently mutated genes in MTBC reveal expected and newly discovered in host adaptations, predominantly associated with DR but also with pathogenesis. The higher resistance acquisition rate observed for fluoroquinolones may have important clinical relevance.The authors applied a within-host evolutionary approach to show that frequently mutated genes in Mycobacterium tuberculosis complex strains reveal expected and newly discovered in host adaptations, predominantly related to drug resistance but also in genes of the virulence ESX-1 locus.