The gene controls sensitivity of the bacterium to hydrogen peroxide

Hu, Yan; Kendall, Sharon L.; Stoker, Neil G.; Coates, Anthony R. M.

doi:10.1016/j.femsle.2004.07.005

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…Amongst these genes are several regulators including the stress response sigma factors sigF and sigJ and the transcriptional regulators whiB1 and whiB6 . Although previous studies have failed to find an in vitro growth effect for either sigF [28,28] or sigJ [29] mutants our results indicate that the genes are involved in the switch from slow to fast growth rate. Sig F mutants have reduced lethality in both mouse [28] and guinea pig models [30] of TB and also have altered cell membrane properties [31], [32] whereas sig J is dispensable for in vivo growth but appears to be involved in protection against hydrogen peroxide [29].…”

Section: Resultscontrasting

confidence: 82%

The Genetic Requirements for Fast and Slow Growth in Mycobacteria

et al. 2009

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Mycobacterium tuberculosis infects a third of the world's population. Primary tuberculosis involving active fast bacterial replication is often followed by asymptomatic latent tuberculosis, which is characterised by slow or non-replicating bacteria. Reactivation of the latent infection involving a switch back to active bacterial replication can lead to post-primary transmissible tuberculosis. Mycobacterial mechanisms involved in slow growth or switching growth rate provide rational targets for the development of new drugs against persistent mycobacterial infection. Using chemostat culture to control growth rate, we screened a transposon mutant library by Transposon site hybridization (TraSH) selection to define the genetic requirements for slow and fast growth of Mycobacterium bovis (BCG) and for the requirements of switching growth rate. We identified 84 genes that are exclusively required for slow growth (69 hours doubling time) and 256 genes required for switching from slow to fast growth. To validate these findings we performed experiments using individual M. tuberculosis and M. bovis BCG knock out mutants. We have demonstrated that growth rate control is a carefully orchestrated process which requires a distinct set of genes encoding several virulence determinants, gene regulators, and metabolic enzymes. The mce1 locus appears to be a component of the switch to slow growth rate, which is consistent with the proposed role in virulence of M. tuberculosis. These results suggest novel perspectives for unravelling the mechanisms involved in the switch between acute and persistent TB infections and provide a means to study aspects of this important phenomenon in vitro.

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Section: Resultscontrasting

confidence: 82%

The Genetic Requirements for Fast and Slow Growth in Mycobacteria

et al. 2009

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“…The WT, YHΔ tpx and YH tpx Comp M. tuberculosis H37Rv strains were grown in 7H9 broth without disturbance for 100 days as described previously [35]. The viability of these strains was determined by CFU counts at different time points.…”

Section: Resultsmentioning

confidence: 99%

Acute and Persistent Mycobacterium tuberculosis Infections Depend on the Thiol Peroxidase TPX

Coates

2009

PLoS ONE

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The macrophage is the natural niche of Mycobacterium tuberculosis infection. In order to combat oxidative and nitrosative stresses and persist in macrophages successfully, M. tuberculosis is endowed with a very efficient antioxidant complex. Amongst these antioxidant enzymes, TpX is the only one in M. tuberculosis with sequence homology to thiol peroxidase. Previous reports have demonstrated that the M. tuberculosis TpX protein functions as a peroxidase in vitro. It is the dominant antioxidant which protects M. tuberculosis against oxidative and nitrosative stresses. The level of the protein increases in oxidative stress. To determine the roles of tpx gene in M. tuberculosis survival and virulence in vivo, we constructed an M. tuberculosis strain lacking the gene. The characteristics of the mutant were examined in an in vitro stationary phase model, in response to stresses; in murine bone marrow derived macrophages and in an acute and an immune resistant model of murine tuberculosis. The tpx mutant became sensitive to H2O2 and NO compared to the wild type strain. Enzymatic analysis using bacterial extracts from the WT and the tpx mutant demonstrated that the mutant contains reduced peroxidase activity. As a result of this, the mutant failed to grow and survive in macrophages. The growth deficiency in macrophages became more pronounced after interferon-γ activation. In contrast, its growth was significantly restored in the macrophages of inducible nitric oxide synthase (iNOS or NOS2) knockout mice. Moreover, the tpx mutant was impaired in its ability to initiate an acute infection and to maintain a persistent infection. Its virulence was attenuated. Our results demonstrated that tpx is required for M. tuberculosis to deal with oxidative and nitrosative stresses, to survive in macrophages and to establish acute and persistent infections in animal tuberculosis models.

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“…Within Mycobacterium bovis , the expression of sigF has been found to be up-regulated in response to a variety of stresses, including antibiotic stress, nutrient depletion and oxidative stress [44]. Similarly, the expression of sigJ in M. tuberculosis is also induced by oxidative stress [45]. It is tempting to hypothesise that MAP strains that contain multiple copies of the sigE , sigJ and sigF transcriptional regulators may exhibit superior ability to mediate the host inflammatory and stress responses, which, in turn, may impart a superior ability to persist with the intracellular environment.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Zoonotic Potential of Mycobacterium avium Subspecies paratuberculosis through Comparative Genomics

et al. 2011

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A comparative genomics approach was utilised to compare the genomes of Mycobacterium avium subspecies paratuberculosis (MAP) isolated from early onset paediatric Crohn's disease (CD) patients as well as Johne's diseased animals. Draft genome sequences were produced for MAP isolates derived from four CD patients, one ulcerative colitis (UC) patient, and two non-inflammatory bowel disease (IBD) control individuals using Illumina sequencing, complemented by comparative genome hybridisation (CGH). MAP isolates derived from two bovine and one ovine host were also subjected to whole genome sequencing and CGH. All seven human derived MAP isolates were highly genetically similar and clustered together with one bovine type isolate following phylogenetic analysis. Three other sequenced isolates (including the reference bovine derived isolate K10) were genetically distinct. The human isolates contained two large tandem duplications, the organisations of which were confirmed by PCR. Designated vGI-17 and vGI-18 these duplications spanned 63 and 109 open reading frames, respectively. PCR screening of over 30 additional MAP isolates (3 human derived, 27 animal derived and one environmental isolate) confirmed that vGI-17 and vGI-18 are common across many isolates. Quantitative real-time PCR of vGI-17 demonstrated that the proportion of cells containing the vGI-17 duplication varied between 0.01 to 15% amongst isolates with human isolates containing a higher proportion of vGI-17 compared to most animal isolates. These findings suggest these duplications are transient genomic rearrangements. We hypothesise that the over-representation of vGI-17 in human derived MAP strains may enhance their ability to infect or persist within a human host by increasing genome redundancy and conferring crude regulation of protein expression across biologically important regions.

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The gene controls sensitivity of the bacterium to hydrogen peroxide

Cited by 9 publications

References 21 publications

The Genetic Requirements for Fast and Slow Growth in Mycobacteria

The Genetic Requirements for Fast and Slow Growth in Mycobacteria

Acute and Persistent Mycobacterium tuberculosis Infections Depend on the Thiol Peroxidase TPX

Exploring the Zoonotic Potential of Mycobacterium avium Subspecies paratuberculosis through Comparative Genomics

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