Appropriate DevR (DosR)-Mediated Signaling Determines Transcriptional Response, Hypoxic Viability and Virulence of Mycobacterium tuberculosis

Majumdar, S De and Vashist, A and Dhingra, S and Gupta, R and Singh, A and Challu, V K and Ramanathan, V D and Kumar, P and Tyagi, J S (2012) Appropriate DevR (DosR)-Mediated Signaling Determines Transcriptional Response, Hypoxic Viability and Virulence of Mycobacterium tuberculosis. PLoS One, 7 (4). e35847. ISSN Electronic: 1932-6203

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Abstract

Background: The DevR(DosR) regulon is implicated in hypoxic adaptation and virulence of Mycobacterium tuberculosis. The present study was designed to decipher the impact of perturbation in DevR-mediated signaling on these properties. Methodology/Principal Findings: M. tb complemented (Comp) strains expressing different levels of DevR were constructed in Mut1* background (expressing DevR N-terminal domain in fusion with AphI (DevRN-Kan) and in Mut2DdevR background (deletion mutant). They were compared for their hypoxia adaptation and virulence properties. Diverse phenotypes were noted; basal level expression (,5.362.3 mM) when induced to levels equivalent to WT levels (,25.869.3 mM) was associated with robust DevR regulon induction and hypoxic adaptation (Comp 9* and 10*), whereas low-level expression (detectable at transcript level) as in Comp 11* and Comp15 was associated with an adaptation defect. Intermediate-level expression (,3.361.2 mM) partially restored hypoxic adaptation functions in Comp2, but not in Comp1* bacteria that coexpressed DevRN-Kan. Comp* strains in Mut1* background also exhibited diverse virulence phenotypes; high/very low-level DevR expression was associated with virulence whereas intermediate-level expression was associated with low virulence. Transcription profiling and gene expression analysis revealed up-regulation of the phosphate starvation response (PSR) in Mut1* and Comp11* bacteria, but not in WT/Mut2DdevR/other Comp strains, indicating a plasticity in expression pathways that is determined by the magnitude of signaling perturbation through DevRN-Kan. Conclusions/Significance: A minimum DevR concentration of ,3.361.2 mM (as in Comp2 bacteria) is required to support HspX expression in the standing culture hypoxia model. The relative intracellular concentrations of DevR and DevRN-Kan appear to be critical for determining dormancy regulon induction, hypoxic adaptation and virulence. Dysregulated DevRNKan- mediated signaling selectively triggers the PSR in bacteria expressing no/very low level of DevR. Our findings illustrate the important role of appropriate two-component- mediated signaling in pathogen physiology and the resilience of bacteria when such signaling is perturbed.

Affiliation:	ICMR-National Institute for Research in Tuberculosis
Item Type:	Article
Uncontrolled Keywords:	DevR (DosR), Hypoxic Viability, Virulence, Mycobacterium tuberculosis
Subjects:	Tuberculosis > Laboratory Research > Pathological
Divisions:	Basic Science Research > Clinical Pathology
Depositing User:	Dr. Rathinasabapati R
Date Deposited:	01 Sep 2022 09:58
Last Modified:	01 Sep 2022 09:58
URI:	http://eprints.nirt.res.in/id/eprint/1149

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