Mycobacterium bovis
 BCG Vaccine Strains Lack
 narK2
 and
 narX
 Induction and Exhibit Altered Phenotypes during Dormancy

Honaker, Ryan W.; Stewart, Amanda L.; Schittone, Stephanie A.; Izzo, Angelo A.; Klein, Michél R.; Voskuil, Martin I.

doi:10.1128/iai.01235-07

Cited by 37 publications

(40 citation statements)

References 40 publications

(75 reference statements)

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“…Cultures treated with NO were exposed to 0.1 mM NO donor diethylenetriamine/NO adduct (Sigma) for 1 h. Growth of bacterial cultures was assayed via OD determination and CFU counting as previously described (16). Experiments were repeated thrice with independently grown cultures.…”

Section: Methodsmentioning

confidence: 99%

Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy

et al. 2009

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In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state.

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Section: Methodsmentioning

confidence: 99%

Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy

et al. 2009

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“…Low oxygen tension, nitric oxide, and carbon monoxide activate a three-component regulatory system comprised of two sensor kinases, DosS (Rv3132c) and DosT (Rv2027c), and a response regulator, DosR (Rv3133c) (21,34,38,(46)(47)(48). DosR-DosS is the dormancy regulon, which has been studied in M. tuberculosis, M. bovis (19), and M. smegmatis (5,25). For M. tuberculosis and M. bovis, not only DosS, but also DosT, was shown to be a sensor kinase for DosR (17,18,42).…”

mentioning

confidence: 99%

Comparative Genomics of the Dormancy Regulons in Mycobacteria

et al. 2011

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In response to stresses, Mycobacterium cells become dormant. This process is regulated by the DosR transcription factor. In Mycobacterium tuberculosis, the dormancy regulon is well characterized and contains the dosR gene itself and dosS and dosT genes encoding DosR kinases, nitroreductases (acg; Rv3131), diacylglycerol acyltransferase (DGAT) (Rv3130c), and many universal stress proteins (USPs). In this study, we apply comparative genomic analysis to characterize the DosR regulons in nine Mycobacterium genomes, Rhodococcus sp. RHA1, Nocardia farcinica, and Saccharopolyspora erythraea. The regulons are highly labile, containing eight core gene groups (regulators, kinases, USPs, DGATs, nitroreductases, ferredoxins, heat shock proteins, and the orthologs of the predicted kinase [Rv2004c] from M. tuberculosis) and 10 additional genes with more restricted taxonomic distribution that are mostly involved in anaerobic respiration. The largest regulon is observed in M. marinum and the smallest in M. abscessus. Analysis of large gene families encoding USPs, nitroreductases, and DGATs demonstrates a mosaic distribution of regulated and nonregulated members, suggesting frequent acquisition and loss of DosR-binding sites.Mycobacterium tuberculosis is a dangerous human pathogen infecting nearly one-third of the human population (1). An important feature of tuberculosis is the prevalence of latent infection without disease manifestation (14). During latency, M. tuberculosis is believed to exist in a state of nonreplicating persistence with low metabolic activity (40,46,49). Understanding the mechanisms used by M. tuberculosis to exist in this state and to switch to a metabolically active, infectious form is an important problem in tuberculosis research.M. tuberculosis is an obligate aerobe; under hypoxia, it ceases growth, decreases protein and RNA synthesis, and enters a dormant state (48,49). Low oxygen tension, nitric oxide, and carbon monoxide activate a three-component regulatory system comprised of two sensor kinases, DosS (Rv3132c) and DosT (Rv2027c), and a response regulator, DosR (Rv3133c) (21,34,38,(46)(47)(48). DosR-DosS is the dormancy regulon, which has been studied in M. tuberculosis, M. bovis (19), and M. smegmatis (5, 25). For M. tuberculosis and M. bovis, not only DosS, but also DosT, was shown to be a sensor kinase for DosR (17,18,42). DosR activates transcription of genes that allow bacteria to survive long periods of anaerobiosis and hence may be important for long-term survival within the host during latent infection (3,7,13,18,34,35).Both kinases, DosT and DosS, respond to nitric oxide, but DosT is more important at the early stage of hypoxia. When oxygen becomes limited, DosT becomes less prominent in the regulatory cascade and DosS alone maintains induction of the dormancy regulon (18,22,23,50). As with many other twocomponent systems, the dosRS operon is autoregulated (2). The DosR-binding motif, an 18-bp palindrome, has been found by experiment (45) and by computational analysis of eight DosR-regulate...

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“…In contrast, peripheral blood mononuclear cells from adolescents vaccinated with M. bovis BCG exhibit low responsiveness when stimulated with proteins from the dormancy regulon (94). This may be due to observed differences in dormancy regulon expression between the M. tuberculosis and M. bovis strains (70). Recent evidence also indicates that strains of the highly virulent M. tuberculosis W-Beijing lineage express dosR at elevated levels (3,40,122).…”

Section: Devr-devs-rv2027c or Dosr-doss-dostmentioning

confidence: 92%

Adaptation to Environmental Stimuli within the Host: Two-Component Signal Transduction Systems of Mycobacterium tuberculosis

Bretl

Demetriadou

Zahrt

2011

Microbiol Mol Biol Rev

127

133

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SUMMARY Pathogenic microorganisms encounter a variety of environmental stresses following infection of their respective hosts. Mycobacterium tuberculosis , the etiological agent of tuberculosis, is an unusual bacterial pathogen in that it is able to establish lifelong infections in individuals within granulomatous lesions that are formed following a productive immune response. Adaptation to this highly dynamic environment is thought to be mediated primarily through transcriptional reprogramming initiated in response to recognition of stimuli, including low-oxygen tension, nutrient depletion, reactive oxygen and nitrogen species, altered pH, toxic lipid moieties, cell wall/cell membrane-perturbing agents, and other environmental cues. To survive continued exposure to these potentially adverse factors, M. tuberculosis encodes a variety of regulatory factors, including 11 complete two-component signal transduction systems (TCSSs) and several orphaned response regulators (RRs) and sensor kinases (SKs). This report reviews our current knowledge of the TCSSs present in M. tuberculosis . In particular, we discuss the biochemical and functional characteristics of individual RRs and SKs, the environmental stimuli regulating their activation, the regulons controlled by the various TCSSs, and the known or postulated role(s) of individual TCSSs in the context of M. tuberculosis physiology and/or pathogenesis.

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Mycobacterium bovis BCG Vaccine Strains Lack narK2 and narX Induction and Exhibit Altered Phenotypes during Dormancy

Cited by 37 publications

References 40 publications

Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy

Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy

Comparative Genomics of the Dormancy Regulons in Mycobacteria

Adaptation to Environmental Stimuli within the Host: Two-Component Signal Transduction Systems of Mycobacterium tuberculosis

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