Student project

Genetic characterization of the DosR regulon In Mycobacterium tuberculosis W/Beijing strains

The exact role of the DosR "dormancy" regulon in the pathogenesis of Mycobacterium tuberculosis is still unclear. It has been observed that members of the regulon, including dosR, are constitutively expressed in clinical isolates belonging to the W/Beijing lineage as compared to non-W/Beijing strains. In non-W/Beijing isolates, the DosR regulon is only expressed at high levels in response to low oxygen tension or the presence of nitric oxide (NO). While generating a dosR::hyg mutant in non-W/Beijing (H37Rv) and W/Beijing (HN878 and B.1.2) backgrounds in order to investigate the regulation of the DosR regulon expression within the W/Beijing lineage, the presence of two copies of dosR was observed. Incredibly, while attempting to understand this observation, we identified the presence of a massive   350Kbp tandem duplication that included dosR in HN878 and B.1.2 Beijing strains. A role for IS6110 in the mechanism of the duplication was hypothesized due to the fact that a copy of IS6110 is located at the beginning, the junction and the end of the duplication. Variants of the duplication in clinical isolates of Group 4 and 5 of the W/Beijing lineage were also identified which is consistent with the duplication being relatively unstable. Finally, by qRT-PCR I identified that the expression of dosR and dosS is higher in strains that have the duplication. Surprisingly, the induction of hspX, fdxA, Rv2626c and tgs (all members of the DosR regulon) is lower in those strains, suggesting the presence of unknown additional regulator proteins within the W/Beijing that may regulate induction of the DosR regulon. In conclusion, to the best of my knowledge this is the first example of a duplication within M. tuberculosis, the presence of which regulates induction of the DosR regulon (and presumably many other genes) within strains of the W/Beijing lineage


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