Mycobacterium tuberculosis is less likely to acquire pathogenic mutations during latent infection than during active disease

Most people infected with Mycobacterium tuberculosis (Mtb) are believed to be in a state of latent tuberculosis (TB) infection (LTBI). Although LTBI is asymptomatic and not infectious, there is a risk of developing active disease even decades after infection. Here, to characterize mutations acquired during LTBI, we collected and analyzed Mtb genomes from seven Japanese patient pairs, each pair consisting of two active TB patients whose starting dates of developing active disease were >3 years apart; one had a high suspicion of LTBI before developing active disease, whereas the other did not. Thereafter, we compared these genomes with those of longitudinal sample pairs within a host of chronic active TB infections combined with public data. The bacterial populations in patients with LTBI were genetically more homogeneous and accumulated single nucleotide polymorphisms (SNPs) slower than those from active disease. Moreover, the lower proportion of nonsynonymous SNPs indicated weaker selective pressures during LTBI than active disease. Finally, the different mutation spectrums indicated different mutators between LTBI and active disease. These results suggest that the likelihood of the acquisition of mutations responsible for antibiotic resistance and increased virulence was lower in the Mtb population from LTBI than active disease. IMPORTANCE Controlling latent tuberculosis (TB) infection (LTBI) activation is an effective strategy for TB elimination, where understanding Mycobacterium tuberculosis (Mtb) dynamics within the host plays an important role. Previous studies on chronic active disease reported that Mtb accumulated genomic mutations within the host, possibly resulting in acquired drug resistance and increased virulence. However, several reports suggest that fewer mutations accumulate during LTBI than during the active disease, but the associated risk is largely unknown. Here, we analyzed the genomic dynamics of Mtb within the host during LTBI. Our results statistically suggest that Mtb accumulates mutations during LTBI, but most mutations are under low selective pressures, which induce mutations responsible for drug resistance and virulence. Thus, we propose that LTBI acts as a source for new TB disease rather than as a period for in-host genome evolution.