From environmental bacteria to obligate pathogen: the study of adaptations enhancing the persistence of tuberculosis bacilli
Mycobacterium tuberculosis is a highly contagious human pathogen that has the capacity to survive for decades within the host. In contrast, Mycobacterium canettii, which is thought to have originated from the same pool of ancestors as M. tuberculosis, rarely causes tuberculosis (TB) in humans and has a reduced capacity to persist and cause disease in the mouse model. To achieve our goal of identifying the genetic adaptations that lead to persistence of TB bacilli within the host, we used an in vivo experimental evolution strategy to amplify M. canettii clones which have enhanced persistence in the mouse model and are therefore phenotypically closer to M. tuberculosis.Genome sequencing of 120 "persistent clones" revealed several mutations likely to be associated with the increased persistence phenotype. Mutations in the rv1339 gene and the esx-5 locus were confirmed to be responsible for the persistence gain observed in vivo, and it was shown that this phenotype was also present in several mouse genetic backgrounds. Two clones were then selected for phenotypic characterisation in vitro and were found to have significantly enhanced resistance to stress encountered during infection of the host. Interestingly, the mutation in the rv1339 gene was found to be responsible for the increased resistance of these "persistent clones" to nitric oxide in comparison to the parental M. canettii strain.We are currently investigating the function of the Rv1339 protein and we believe this will ...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Allen, A. C., Malaga, W., Astarie-Dequeker, C., Hassan, A., Berrone, C., Moreau, F., Supply, P., Brosch, R., Guilhot, C. Tags: Tuberculosis Source Type: research