Loss of oxyR in Mycobacterium tuberculosis

Deretic, Vojo; Song, Jian; Pagán-Ramos, Eileen

doi:10.1016/s0966-842x(97)01112-8

Cited by 51 publications

(49 citation statements)

References 41 publications

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“…One isolate carried a C21A synonymous mutation. Ten isolates also carried the G37A polymorphism in oxyR, which is nonfunctional in M. tuberculosis, carrying multiple deletions and mutations (4); therefore, this mutation is unlikely to confer INH resistance.…”

Section: Discussionmentioning

confidence: 99%

Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam

et al. 2006

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Vietnam is ranked 13th among the WHO list of 22 high-burden countries, based upon estimated total number of tuberculosis cases. Despite having a model national tuberculosis program, consistently achieving and exceeding WHO targets for detection and cure, drug-resistant and multidrug-resistant tuberculosis cases continue to rise. Rapid multidrug-resistant tests applicable in this setting, coupled with effective treatment regimens, would be a useful tool in reversing this trend, allowing early identification of patients with multidrugresistant tuberculosis and avoiding resistance-amplifying regimens. Sequencing of consecutive isolates identified by the National Tuberculosis Program showed 89% of isoniazid-resistant isolates could be detected by targeting just 2 codons, katG 315 and ؊15C3T in the inhA promoter, while rifampin resistance will be more complex to detect, with many different mutation and insertion events in rpoB. The most prevalent rifampin resistance-conferring mutations, as in other countries, were in rpoB codons 531 (43%), 526 (31%), and 516 (15%). However, a hybridization-based resistance test with probes targeting the 5 most common mutations would only detect 78% of rifampin-resistant isolates. Overall, these data suggest that rifampin resistance may be used as a surrogate marker for multidrug-resistant tuberculosis and that a sensitivity of between 70 to 80% may be possible for rapid molecular detection of multidrug-resistant tuberculosis in this setting.

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Section: Discussionmentioning

confidence: 99%

Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam

et al. 2006

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“…(Kirschner et al, 1993 ;Telenti et al, 1993). M. tuberculosis complex organisms have multiple mutations in the oxyR gene, a homologue of the extensively studied central regulator of peroxide stress response in enteric bacteria (Deretic et al, 1997). Because oxyR in M. tuberculosis complex isolates probably does not encode a functional protein, it is referred to as a pseudogene.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of mycobacteria isolated from seals

Zumárraga¹,

Bernardell

Bastida³

et al. 1999

Microbiology

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Tuberculosis (TB) was diagnosed in 10 seals from three species (Arctocephalus australis, Arctocephalus tropicalis and Otaria flavescens) found in South America. The mycobacteria isolated from these cases belonged to the Mycobacterium tuberculosis complex, as determined by RFLP using an IS6110 probe, spoligotyping, analysis of the 16S rRNA gene sequence and by PCRrestriction analysis of hsp65. Polymorphisms in gyrA, katG, oxyR and pncA were investigated in some of the isolates, as well as the presence of the MPB70 antigen. The insertion sequence IS6110 was present in three to seven copies in the genome of the mycobacteria isolated from seals. Using the IS6110 probe, six patterns (designated A, B, C, D, E and F) were identified from 10 different isolates. Patterns A and B were found for the mycobacteria isolated from two and four seals, respectively, indicating an epidemiological relationship between isolates grouped according to their IS6110 RFLP. The mycobacteria isolated from seals shared the majority of their IS6110 DNAcontaining restriction fragments, and nine isolates had an identical spoligotype ; only one isolate showed a minor difference in its spoligotype. In addition, none of these spoligotypes were found in other M. tuberculosis complex strains. These results suggest that the isolates from seals constitute a unique group of closely related strains. The mycobacteria isolated from seals showed polymorphisms at gyrA codon 95 and katG codon 463, as do group 1 M. tuberculosis, and M. bovis. Group 1 mycobacteria are associated with cluster cases. The spoligotypes found in the mycobacteria isolated from seals lack spacers 39-43, as does M. bovis, but the MPB70 antigen, which is highly expressed in M. bovis and minimally expressed in M. tuberculosis, was not detected in these mycobacteria. The mycobacteria isolated from seals also showed oxyR and pncA polymorphisms specific to M. tuberculosis. In conclusion, the mycobacteria that cause TB in seals in the South-Western Atlantic are a related group, and based on the combination of genetic characteristics, belong to a unique genotypic group within the M. tuberculosis complex.

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“…On the bacterial side, M. tuberculosis virulence has been associated with its initial survival within macrophages and resistance to reactive oxygen and nitrogen intermediates (ROIs and RNIs) (5)(6)(7)(8). Tubercle bacilli demonstrate inducible responses to oxidative stresses, and several M. tuberculosis genes, including katG (catalase peroxidase), ahpC (alkylhydroperoxide reductase), and sodA and sodC (superoxide dismutases) have been implicated in protection from the macrophage oxidative burst (9)(10)(11).…”

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Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

Kaushal

Schroeder

Tyagi

et al. 2002

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

220

228

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The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL͞6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4 ؉ and CD8 ؉ T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.T uberculosis is one of the leading infectious causes of death and claims Ϸ2 million lives annually (1). There is controversy over whether the disease is primarily a dysfunctional immunologic reaction to a persistent microbe or whether the bacteria themselves produce tissue damage; there is evidence that both host and bacterial factors play key roles in disease severity. In susceptible mouse strains, such as C3H, the pathogen elicits a dysregulated, necrotizing host immune response leading to tissue destruction and further bacterial replication. In resistant mice such as C57BL͞6, Mycobacterium tuberculosis survives in high numbers for many months and is contained in organized granulomatous lesions in the lung without progressive lung damage. Thus whereas mycobacteria survive in both genetic backgrounds, disease progression is delayed in resistant animals (2-4).On the bacterial side, M. tuberculosis virulence has been associated with its initial survival within macrophages and resistance to reactive oxygen and nitrogen intermediates (ROIs and RNIs) (5-8). Tubercle bacilli demonstrate inducible responses to oxidative stresses, and several M. tuberculosis genes, including katG (catalase peroxidase), ahpC (alkylhydroperoxide reductase), and sodA and sodC (superoxide dismutases) have been implicated in protection from the macrophage oxidative burst (9-11). Another potential ...

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Loss of oxyR in Mycobacterium tuberculosis

Cited by 51 publications

References 41 publications

Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam

Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam

Molecular characterization of mycobacteria isolated from seals

Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

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