<i>Mycobacterium tuberculosis</i>
            WhiB3 responds to O
            <sub>2</sub>
            and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival

Singh, Amit; Guidry, Loni; Narasimhulu, K.; Mai, Deborah; Trombley, John E.; Redding, Kevin; Giles, Gregory I.; Lancaster, Jack R.; Steyn, Adrie J. C.

doi:10.1073/pnas.0700490104

Cited by 179 publications

(255 citation statements)

References 28 publications

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“…2). Recently, Singh et al (2007) suggested that WhiB3 responded to the dormancy signals, NO and O 2, through its iron-sulfur cluster. The RegX3 has also been reported to participate in the adaptation to the host environment (Parish et al 2003).…”

Section: Detection Of New Transcription Regulators For the Expressionmentioning

confidence: 99%

“…Since WhiB3 holds an iron-sulfur (Fe-S) cluster to respond to the stress signals NO and O 2 , Singh et al have suggested that WhiB3 might be a metabolic switching and intracellular redox sensor in M. tuberculosis (Singh et al 2007). Our finding that WhiB3 could extensively regulate fatty acid metabolism and stress responses by binding directly with their promoter sequence supported and extended this conclusion.…”

Section: Detection Of New Transcription Regulators For the Expressionmentioning

confidence: 99%

“…The induction of genes involved in the b-oxidation of fatty acids during M. tuberculosis persistent infections suggests that fatty acids might be a major source of carbon and energy in chronically infected lung tissue (Sassetti and Rubin 2003). In addition to this, M. tuberculosis appears to have sophisticated genetic mechanisms to recognize stressful environment signals, such as O 2 , NO, and fluctuations in the intracellular redox state (Singh et al 2007). The genes involved in fatty acid metabolism and stress responses have been suggested to comprise the core of in vivo-regulated genes (Talaat et al 2004).…”

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confidence: 99%

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Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system

Guo¹,

Feng²,

Zhang³

et al. 2009

Genome Res.

123

211

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Sequence-specific DNA-binding transcription factors have widespread biological significance in the regulation of gene expression. However, in lower prokaryotes and eukaryotic metazoans, it is usually difficult to find transcription regulatory factors that recognize specific target promoters. To address this, we have developed in this study a new bacterial one-hybrid reporter vector system that provides a convenient and rapid strategy to determine the specific interaction between target DNA sequences and their transcription factors. Using this system, we have successfully determined the DNA-binding specificity of the transcription regulator Rv3133c to a previously reported promoter region of the gene Rv2031 in Mycobacterium tuberculosis. In addition, we have tested more than 20 promoter regions of M. tuberculosis genes using this approach to determine if they interact with ;150 putative regulatory proteins. A variety of transcription factors are found to participate in the regulation of stress response and fatty acid metabolism, both of which comprise the core of in vivo-induced genes when M. tuberculosis invades macrophages. Interestingly, among the many new discovered potential transcription factors, the WhiB-like transcriptional factor WhiB3 was identified for the first time to bind with the promoter sequences of most in vivo-induced genes. Therefore, this study offers important data in the dissection of the transcription regulations in M. tuberculosis, and the strategy should be applicable in the study of DNA-binding factors in a wide range of biological organisms.

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Section: Detection Of New Transcription Regulators For the Expressionmentioning

confidence: 99%

Section: Detection Of New Transcription Regulators For the Expressionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system

Guo¹,

Feng²,

Zhang³

et al. 2009

Genome Res.

123

211

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“…79 For example, WhiB3 was shown to interact with SigA 77 and responds to oxygen and nitric oxide, and is important for regulation of carbon metabolism. 80 TrcR is the response regulator of the TrcR-TrcS two-component system. Characterization of these genes is ongoing, but deletion of trcS from M. tb generates a hypervirulent phenotype such that the strain exhibits increased lethality in SCID mice.…”

Section: Attenuation Of Bcg After 1924mentioning

confidence: 99%

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Liu

Tran²,

Leung³

et al. 2009

Human Vaccines

125

117

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by MDR strains that are also resistant to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin), caught the world's attention after an outbreak in KwaZulu-Natal, South Africa, where 52 of 53 infected patients died. 2 HIV co-infection was a contributing factor in most of these deaths, and indeed, a deadly association between HIV and TB has been known almost since the start of the HIV-epidemic. Of the 1.7 million people who died from TB in 2006, an estimated 200,000 were co-infected with HIV. 1 Because of these situations, effective approaches alternative to antibiotics are urgently needed for the control of TB.Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis (M. bovis), is currently the only available vaccine against TB. Since 1974, BCG vaccination has been included in the WHO Expanded Program on Immunization. 3 It is estimated that more than 3 billion individuals have been immunized with BCG and over 100 million doses of BCG are administered annually, making it the most widely used vaccine in humans. 3 Meta-analysis studies have confirmed that BCG protects children, providing >80% efficacy against severe forms of TB, including tuberculous meningitis and miliary TB. 4,5 In contrast, evidence for protection against pulmonary TB in adolescents and adults remains contentious as efficacy estimates from clinical trials, observational case control studies and contact studies range from 0 to 80%. 6,7 The reasons for the variable protective efficacy are unknown but several hypotheses have been proposed, including differences among the vaccine strains used in clinical studies, exposure of trial populations to environmental mycobacteria, nutritional or genetic differences in human populations, differences in trial methods, and variations among clinical M. tb strains. 8-13 These explanations are not mutually exclusive and all may contribute to the heterogeneity in vaccine efficacy.A key aspect of this issue may concern the nature of BCG attenuation. Although it is generally considered safe and has been used as a human vaccine since the 1920s, the mechanisms of BCG attenuation remain largely unknown. This is further complicated by the fact that BCG is not a single strain, but instead comprises a number of substrains that exhibit phenotypic and biochemical differences. 14 BCG strains also exhibit differences in residual virulence level. [15][16][17] However, side effects were often attributed to variations in the viability of vaccines during preparation procedures (e.g., freezedrying). 14 In other words, the observed differential virulence among Mycobacterium bovis Bacille Calmette-Guérin (BCG) was developed as an attenuated live vaccine for tuberculosis control nearly a century ago. Despite being the most widely used vaccine in human history, the mechanisms of attenuation of BCG remain poorly understood. BCG is not a single organism, but comprises a number of substrains that differ in genotypes and phenotypes. The impacts of these differences on BCG...

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“…Also, despite extensive studies (3)(4)(5), to date, the presumed host ligands of DosS and DosT have not yet been established experimentally nor has it been determined how these sensors modulate signaling. In an accompanying paper (26), we provide evidence that Mtb WhiB3 responds to the host signals O 2 and NO via its [4Fe-4S] cluster. In this article, we believe that ascertaining of host ligands of DosS and DosT and deciphering how the Dos regulon is modulated will lead to a new and better understanding of the mechanism of Mtb persistence.…”

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confidence: 99%

Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor

Kumar¹,

Toledo

Patel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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300

375

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A fundamental challenge to the study of oxidative stress responses of Mycobacterium tuberculosis (Mtb) is to understand how the protective host molecules are sensed and relayed to control bacilli gene expression. The genetic response of Mtb to hypoxia and NO is controlled by the sensor kinases DosS and DosT and the response regulator DosR through activation of the dormancy/NO (Dos) regulon. However, the regulatory ligands of DosS and DosT and the mechanism of signal sensing were unknown. Here, we show that both DosS and DosT bind heme as a prosthetic group and that DosS is rapidly autooxidized to attain the met (Fe 3؉ ) form, whereas DosT exists in the O 2-bound (oxy) form. EPR and UV-visible spectroscopy analysis showed that O 2, NO, and CO are ligands of DosS and DosT. Importantly, we demonstrate that the oxidation or ligation state of the heme iron modulates DosS and DosT autokinase activity and that ferrous DosS, and deoxy DosT, show significantly increased autokinase activity compared with met DosS and oxy DosT. Our data provide direct proof that DosS functions as a redox sensor, whereas DosT functions as a hypoxia sensor, and that O 2, NO, and CO are modulatory ligands of DosS and DosT. Finally, we identified a third potential dormancy signal, CO, that induces the Mtb Dos regulon. We conclude that Mtb has evolved finely tuned redox and hypoxia-mediated sensing strategies for detecting O 2, NO, and CO. Data presented here establish a paradigm for understanding the mechanism of bacilli persistence.carbon monoxide ͉ dormancy ͉ nitric oxide ͉ oxygen ͉ persistence T uberculosis (TB) is a major global health burden, and current estimates suggest that one-third of the world's population (Ϸ2 billion) is latently infected with TB (1). Latency is important largely because persistent Mycobacterium tuberculosis (Mtb) are in a state of ''drug unresponsiveness'' wherein the bacilli are resistant to existing antimycobacterial drugs. A major question in the TB field is: ''what are the mechanisms that allow Mtb to persist in human tissues for decades without replicating, to then abruptly resume growth and cause disease?'' Addressing that question is essential to the development of effective therapeutic intervention strategies. Recent evidence implicates NO as an environmental trigger of mycobacterial persistence (2-5). The latter findings are particularly interesting in light of the fact that inducible NO synthase (iNOS) and therefore NO production is crucial for protection of mice against Mtb (6), and that human macrophages in Mtb-infected tissues express iNOS (2, 7). Another factor associated with latent TB is hypoxia (8). The role of oxygen tension in TB is receiving wide attention, especially because it was demonstrated that rapid withdrawal of oxygen is lethal to Mtb, whereas a gradual depletion allows time for adaptation and bacterial survival (8). Interestingly, a significant overlap exists between the gene expression profiles of Mtb cells treated with NO and that of bacilli cultured under hypoxic conditions (3-5). ...

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Mycobacterium tuberculosis WhiB3 responds to O ₂ and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival

Cited by 179 publications

References 28 publications

Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system

Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor

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Mycobacterium tuberculosis WhiB3 responds to O 2 and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival

Cited by 179 publications

References 28 publications

Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system

Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor

Contact Info

Product

Resources

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Mycobacterium tuberculosis WhiB3 responds to O ₂ and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival