Abstract
BackgroundThe DevR response regulator is implicated in both hypoxic adaptation and virulence of Mycobacterium tuberculosis (M. tb). DevR regulon genes are powerfully induced in vivo implicating them in bacterial adaptation to host control strategies. A better understanding of DevR function will illumine the way for new strategies to control and treat tuberculosis.Methodology/Principal FindingsTowards this objective, we used a combination of genetic, microbiological, biochemical, cell biological tools and a guinea pig virulence assay to compare the hypoxic adaptation and virulence properties of two novel M. tb strains, namely, a devR disruption mutant, Mut1, that expresses C-terminal truncated N-terminal domain of DevR (DevRNTD) as a fusion protein with AphI (DevRN-Kan), and its complemented strain, Comp1, that expresses intact DevR along with DevRN-Kan. Comp1 bacteria exhibit a defect in DevR-mediated phosphosignalling, hypoxic induction of HspX and also hypoxic survival. In addition, we find that Comp1 is attenuated in virulence in guinea pigs and shows decreased infectivity of THP-1 cells. While Mut1 bacilli are also defective in hypoxic adaptation and early growth in spleen, they exhibit an overall virulence comparable to that of wild-type bacteria.Conclusions/SignificanceThe hypoxic defect of Comp1 is associated to a defect in DevR expression level. The demonstrated repression of DevR function by DevRN-Kan suggests that such a knockdown approach could be useful for evaluating the activity of DevRS and other two-component signaling pathways. Further investigation is necessary to elucidate the mechanism underlying Comp1 attenuation.
Highlights
Mycobacterium tuberculosis (M. tb) is a versatile intracellular pathogen that has the ability to either cause active disease or produce a persistent latent infection
M. tb genome sequencing has revealed the presence of a panoply of potential regulatory molecules that comprise of transcriptional regulators, sigma factors and signaling systems including two-component systems (TCS) and eukaryotic-like serine threonine protein kinases/phosphatases [1]
We studied the properties of guinea pig-passaged Mut1 and Comp1 bacteria alongside wild-type H37Rv (WT) bacteria
Summary
Mycobacterium tuberculosis (M. tb) is a versatile intracellular pathogen that has the ability to either cause active disease or produce a persistent latent infection. M. tb genome sequencing has revealed the presence of a panoply of potential regulatory molecules that comprise of transcriptional regulators, sigma factors and signaling systems including two-component systems (TCS) and eukaryotic-like serine threonine protein kinases/phosphatases [1]. All of these are likely to play a dynamic role in bacterial adaptation to the changing environmental conditions within the host. A better understanding of DevR function will illumine the way for new strategies to control and treat tuberculosis
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