Sarah Fortune and colleagues report the whole-genome sequencing of Mycobacterium tuberculosis strains isolated from cynomolgus macaques with either active, latent or early reactivation disease. They estimate a similar mutation rate for these disease states in vivo, as well as for the bacterium in vitro. This suggests that M. tuberculosis has a greater mutational rate during latent and early reactivation disease than previously predicted and may be able to acquire drug resistance during these states. Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance1,2.

Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection