A case of endogenous and collateral reactivation caused by two Mycobacterium tuberculosis subclones

Endogenous reactivation of tuberculosis (TB) has been considered a process in which Mycobacterium tuberculosis subclones continuously accumulate genome mutations from the initial isolate. However, we encountered a case of endogenous reactivation that M. tuberculosis isolated from the primary disease and recurrence collaterally diverging from an original clone. In a retrospective cohort study, a recurrent TB case was thoroughly investigated in 2012 and 2020 in Yamagata, Japan. This included an evaluation of the clinical course, including computed tomography (CT) findings, retrospective contact tracings, molecular epidemiological investigations, and whole-genome sequencing of M. tuberculosis. CT imaging revealed new lesions in different regions of the right lung in 2012 and 2020. Retrospective contact tracings and a molecular epidemiological surveillance using variable-number tandem repeat typing ruled out exogenous reinfection. A genome comparison of two M. tuberculosis isolates cultured in 2012 and 2020 revealed 14 single nucleotide variants, with each accumulating 7 single nucleotide variants from the original clone. These findings provide evidence that M. tuberculosis subclones in different lung lesions within the same host can accumulate genome mutations collaterally. Our case report indicates that recognizing the potential for collateral reactivation may enhance strategies for tracing transmission routes and deepen our understanding of the evolution of drug resistance. Future research should focus on identifying additional cases of collateral reactivation, supported by both pathophysiological and genome microbiological evidence.