DevR–DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR

Saini, Deepak Kumar; Malhotra, Vandana; Dey, Deepanwita; Pant, Neha; Das, Taposh K.; Tyagi, Jaya Sivaswami

doi:10.1099/mic.0.26218-0

Cited by 154 publications

(191 citation statements)

References 29 publications

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“…Altered genes include sigma factors [39,40] and PGRS-encoding genes [41], as well as activation of alternative pathways in the citrate cycle to allow metabolism of the abundant lipids in the necrotic centre of granulomas [42,43] and general adaptation to low oxygen tension [44]. More recently, in vitro studies identified a regulon consisting of two sensor kinases, DosS and DosT, under the control of the transcription factor DosR, which sense and control the host response to hypoxia and nitric oxide stress [45][46][47], thus enabling M. tuberculosis to adapt to local conditions during latency [48] (Figure 5). The DosR system contributes significantly to transition into mycobacterial dormancy in an in vivo model of artificial granulomas in mice [49].…”

Section: Transition Of M Tuberculosis Into a Dormant State Within Grmentioning

confidence: 99%

New insights into the function of granulomas in human tuberculosis

Ulrichs

Kaufmann

2005

The Journal of Pathology

343

337

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The human tuberculous granuloma provides the morphological framework for local immune processes central to the outcome of tuberculosis. This review article describes investigations on human lung granulomas aimed at better understanding the regional host response and counter-measures to Mycobacterium tuberculosis. These findings lead to a revised view of the regional immune response in human tuberculosis. Novel insights into this dynamic cross-talk form the basis of novel intervention strategies.

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Section: Transition Of M Tuberculosis Into a Dormant State Within Grmentioning

confidence: 99%

New insights into the function of granulomas in human tuberculosis

Ulrichs

Kaufmann

2005

The Journal of Pathology

343

337

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“…For example, the expression and activities of dnaA and ftsZ genes in Caulobacter crescentus are modulated by CtrA, an essential 2CR (Kelly et al, 1998;Quon et al, 1998;Stephens, 1999;Wortinger et al, 2000). It is also known that devR, a nonessential 2CR gene, is important for the regulation of the hypoxic response (Sherman et al, 2001;O'Toole et al, 2003;Saini et al, 2004) and for maintaining the bacterium in a non-replicative persistent state (Wayne, 1977;1994;Wayne and Hayes, 1996).…”

Section: Expression Of Select M Tuberculosis Genes During Intramacromentioning

confidence: 99%

Modulation of Mycobacterium tuberculosis proliferation by MtrA, an essential two‐component response regulator

Fol

Chauhan

Nair

et al. 2006

Molecular Microbiology

146

192

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SummaryPaired two-component regulatory systems consisting of a sensor kinase and a response regulator are the major means by which bacteria sense and respond to different stimuli. The role of essential response regulator, MtrA, in Mycobacterium tuberculosis proliferation is unknown. We showed that elevating the intracellular levels of MtrA prevented M. tuberculosis from multiplying in macrophages, mice lungs and spleens, but did not affect its growth in broth. Intracellular trafficking analysis revealed that a vast majority of MtrA overproducing merodiploids were associated with lysosomal associated membrane protein (LAMP-1) positive vacuoles, indicating that intracellular growth attenuation is, in part, due to an impaired ability to block phagosome-lysosome fusion. A merodiploid strain producing elevated levels of phosphorylation-defective MtrA (MtrA D53N ) was partially replicative in macrophages, but was attenuated in mice. Quantitative real-time PCR analyses revealed that expression of dna A, an essential replication gene, was sharply upregulated during intramacrophage growth in the MtrA overproducer in a phosphorylation-dependent manner. Chromatin immunoprecipitation using anti-MtrA antibodies provided direct evidence that MtrA regulator binds to dna A promoter in vivo indicating that dna A promoter is a MtrA target. Simultaneous overexpression of mtr A regulator and its cognate mtr B kinase neither inhibited growth nor sharply increased the expression levels of dna A in macrophages. We propose that proliferation of M. tuberculosis in vivo depends, in part, on the optimal ratio of phosphorylated to nonphosphorylated MtrA response regulator.

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“…An in vitro model of bacterial dormancy under hypoxia was described first by Wayne's laboratory (Wayne & Hayes, 1996). Subsequent variations of the hypoxia model were introduced, including the standing of cultures in tube and plate formats (Hu et al, 1998;Saini et al, 2004), the rapid generation of defined hypoxia (Sherman et al, 2001) and bacterial culturing in vented cap flasks under low oxygen tension (Florczyk et al, 2003). The survival mechanisms adopted by intracellular Mtb under conditions of nutrient limitation were delineated in an in vitro nutrient starvation model (Loebel et al, 1933;Betts et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The pleiotropic transcriptional response of Mycobacterium tuberculosis to vitamin C is robust and overlaps with the bacterial response to multiple intracellular stresses

et al. 2015

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Mycobacterium tuberculosis (Mtb) owes its success as a pathogen in large measure to its ability to exist in a persistent state of 'dormancy' resulting in a lifelong latent tuberculosis (TB) infection. An understanding of bacterial adaptation during dormancy will help in devising approaches to counter latent TB infection. In vitro models have provided valuable insights into bacterial adaptation; however, they have limitations because they do not disclose the bacterial response to the intracellular environment wherein the bacteria are simultaneously exposed to multiple stresses. We describe the pleiotropic response of Mtb in the vitamin C (vit C) model of dormancy developed in our laboratory. Vit C mediates a rapid regulation of genes representing~14 % of the genome in Mtb cultures. The upregulated genes were better represented in lipid, intermediary metabolism and regulatory protein categories. The downregulated genes mainly related to virulence, detoxification, information pathways and cell wall processes. A comparison of this response to that in other models indicates that vit C generates a multiple-stress environment for axenic Mtb cultures that resembles a macrophage-like environment. The bacterial response to vit C resembles responses to gaseous stresses such as hypoxia and nitric oxide, oxidative and nitrosative stresses, nutrient starvation and, notably, the activated macrophage environment itself. These responses demonstrate that the influence of vit C on Mtb gene expression extends well beyond the DevR dormancy regulon. A detailed characterization of the response to vit C is expected to disclose useful strategies to counter the adaptive mechanisms essential to Mtb dormancy.

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DevR–DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR

Cited by 154 publications

References 29 publications

New insights into the function of granulomas in human tuberculosis

New insights into the function of granulomas in human tuberculosis

Modulation of Mycobacterium tuberculosis proliferation by MtrA, an essential two‐component response regulator

The pleiotropic transcriptional response of Mycobacterium tuberculosis to vitamin C is robust and overlaps with the bacterial response to multiple intracellular stresses

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