Substantial Molecular Evolution In Prolonged Latent Mycobacterium Tuberculosis Infections In Humans

Introduction: Despite its central role as a reservoir for active tuberculosis disease (TB), latent Mycobacterium tuberculosis (Mtb) infections and the underlying persistence mechanisms are poorly understood. The Mtb genome in latently infected individuals may hold the key to understanding the processes that lead to reactivation and progression to clinical disease. Methods: We studied genomic relationships among 14 isolates of Mtb from historical and recent Danish clinical strain collections, spanning more than three decades, to investigate 6 putative cases of Mtb reactivation, inferred from IS6110 profiles. Single-nucleotide polymorphism (SNPs) patterns were analyzed to identify true cases of TB re-activation, as well as the underlying mutational patterns. Results: Two parallel cases of latent TB reactivation were identified. We found an average mutation rate of 0.2 – 0.3 over 33 years, as well as evidence for distinct processes such as oxidative damage or natural selection having contributed to mutation accumulation. Conclusions: Our study shows that distinct processes can shape Mtb genomes during latent infection. Most importantly, we document substantial molecular evolution of Mtb over three decades, with mutation rates similar to observations from cases of active disease. Our study thus emphasizes the importance of identifying and controlling latent cases.