Mycobacterial Growth and Dormancy

Colston, M. Joseph; Cox, Robert A.

doi:10.1002/9781444311433.ch11

Cited by 16 publications

(15 citation statements)

References 40 publications

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“…The genes inactivated in WAg523 clearly had a phenotypic effect expressed under the screening regime but this had little apparent effect on virulence of WAg523 in guinea pigs. The guinea pig model gives a measure of acute disease and one possible explanation is that, given the way the strain was selected, the mutation has affected the ability of the strain to cause reactivation tuberculosis, a property that could only be tested in a reactivation animal model such as the Cornell model (Colston & Cox, 1999). A superficial argument against this explanation is that both of these genes are absent from M. tuberculosis CDC1551, a recent clinical isolate (Betts et al, 2000).…”

Section: Analysis Of Mutations In Relation To Virulencementioning

confidence: 99%

“…Re-examination of procedures revealed the mutants in the study had been subcultured into minimal medium from 5-to 10-week-old cultures in complete medium, at a stage when they would have been in stationary growth. Since the ability of strains of the M. tuberculosis complex to survive in the host in a stationary or lowered metabolic state is regarded as a crucial facet of tuberculosis pathogenesis (Colston & Cox, 1999), we reasoned that it might be desirable to have a vaccine strain without this ability.…”

Section: M Collins and Othersmentioning

confidence: 99%

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Production of avirulent mutants of Mycobacterium bovis with vaccine properties by the use of illegitimate recombination and screening of stationary-phase cultures

et al. 2002

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A better tuberculosis vaccine is urgently required to control the continuing epidemic. Molecular techniques are now available to produce a better live vaccine than BCG by producing avirulent strains of the Mycobacterium tuberculosis complex with known gene deletions. In this study, 1000 illegitimate recombinants of Mycobacterium bovis were produced by illegitimate recombination with fragments of mycobacterial DNA containing a kanamycin resistance gene. Eight recombinant strains were selected on the basis of their inability to grow when stationary-phase cultures were inoculated into minimal medium. Five of these recombinants were found to be avirulent when inoculated into guinea pigs. Two of the avirulent recombinants produced vaccine efficacy comparable to BCG against an aerosol challenge in guinea pigs with M. bovis. One of these recombinants had an inactivated glnA2 gene encoding a putative glutamine synthetase. Transcriptional analysis showed that inactivation of glnA2 did not affect expression of the downstream glnE gene. The other recombinant had a block of 12 genes deleted, including the sigma factor gene sigG. Two avirulent recombinants with an inactivated pckA gene, encoding phosphoenolpyruvate carboxykinase which catalyses the first step of gluconeogenesis, induced poor protection against tuberculosis. It is clear that live avirulent strains of the M. tuberculosis complex vary widely in their ability as vaccines to protect against tuberculosis. Improved models may be required to more clearly determine the difference in protective effect between BCG and potential new tuberculosis vaccines.

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Section: Analysis Of Mutations In Relation To Virulencementioning

confidence: 99%

Section: M Collins and Othersmentioning

confidence: 99%

Production of avirulent mutants of Mycobacterium bovis with vaccine properties by the use of illegitimate recombination and screening of stationary-phase cultures

et al. 2002

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“…a The number of genomes per cell was calculated by use of the formula described in the text, using the values C ϭ 10.33 h and D ϭ 6 h (8,10,23).…”

Section: 07mentioning

confidence: 99%

“…By using these values and the molecular weight of RNAs in an M. tuberculosis ribosome, we could estimate the number of ribosomes per cell (9). In addition, under steady-state growth conditions and assuming negligible or constant protein turnover, the ribosome efficiency could be shown to equal ⅐ P/R, where is the specific growth rate and P and R are the amount of cellular protein and the ribosome content (number of ribosomes), respectively (6,10). According to such calculations, the slowly growing cells contained 687 ribosomes with an efficiency of 0.00055 fg of protein synthesized per ribosome per h, and the fast growing cells contained 3,880 ribosomes with an efficiency of 0.00056.…”

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Compiling a Molecular Inventory for Mycobacterium bovis BCG at Two Growth Rates: Evidence for Growth Rate-Mediated Regulation of Ribosome Biosynthesis and Lipid Metabolism

et al. 2005

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An experimental system of Mycobacterium tuberculosis growth in a carbon-limited chemostat has been established by the use of Mycobacterium bovis BCG as a model organism. For this model, carbon-limited chemostats with low concentrations of glycerol were used to simulate possible growth rates during different stages of tuberculosis. A doubling time of 23 h (D ‫؍‬ 0.03 h ؊1 ) was adopted to represent cells during the acute phase of infection, whereas a lower dilution rate equivalent to a doubling time of 69 h (D ‫؍‬ 0.01 h ؊1 ) was used to model mycobacterial persistence. This chemostat model allowed the specific response of the mycobacterial cell to carbon limitation at different growth rates to be elucidated. The macromolecular (RNA, DNA, carbohydrate, and lipid) and elemental (C, H, and N) compositions of the biomass were determined for steady-state cultures, revealing that carbohydrates and lipids comprised more than half of the dry mass of the BCG cell, with only a quarter of the dry weight consisting of protein and RNA. Consistent with studies of other bacteria, the specific growth rate impacts on the macromolecular content of BCG and the proportions of lipid, RNA, and protein increased significantly with the growth rate. The correlation of RNA content with the growth rate indicates that ribosome production in carbon-limited M. bovis BCG cells is subject to growth rate-dependent control. The results also clearly show that the proportion of lipids in the mycobacterial cell is very sensitive to changes in the growth rate, probably reflecting changes in the amounts of storage lipids. Finally, this study demonstrates the utility of the chemostat model of mycobacterial growth for functional genomic, physiology, and systems biology studies.With three million people dying from tuberculosis (TB) annually, Mycobacterium tuberculosis remains a formidable pathogen. Tuberculosis ranks among the top 10 causes of global mortality and morbidity and is the leading cause of infectious disease (66). The ability of M. tuberculosis to adapt to and survive harsh environmental conditions in order to establish and maintain long-term infections within its human host is fundamental to this organism's success. Modification of the mycobacterial cell in response to changes in the environment is crucial to this adaptive process, but detailed information about how M. tuberculosis changes its macromolecular composition in response to its environment and growth rate is lacking.The genome sequence of M. tuberculosis has been available since 1998 (9). Although information obtained from the genome sequence provided new and valuable insights into the biology of the tubercle bacillus, the genome itself provides few clues regarding how the pathogen responds to its environment by changing its cellular composition. One of the principal tasks of postgenomic biological studies of M. tuberculosis is to understand how the genome orchestrates the structure and dynamics of the cell in response to changes in the environment. This task requires an integrat...

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Slow growth rate of mycobacteria

Lewin

Sharbati

2005

Bundesgesundheitsbl - Gesundheitsforsch - Gesundheitsschutz

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A characteristic feature of mycobacteria is their slow growth rate, which in addition strongly varies in different species of the genus. All highly pathogenic species such as M. tuberculosis and M. leprae causing tuberculosis and leprosy, respectively, belong to the slow growing mycobacteria, while the apathogenic and opportunistic species are members of the fast growing mycobacteria. This suggests that the question be posed whether there is causality between mycobacterial growth rate and virulence. We discuss possible reasons for the slow and variable growth rates of mycobacteria and the current state of knowledge concerning the significance of slow growth for mycobacterial pathogenicity.

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Mycobacterial Growth and Dormancy

Cited by 16 publications

References 40 publications

Production of avirulent mutants of Mycobacterium bovis with vaccine properties by the use of illegitimate recombination and screening of stationary-phase cultures

Production of avirulent mutants of Mycobacterium bovis with vaccine properties by the use of illegitimate recombination and screening of stationary-phase cultures

Compiling a Molecular Inventory for Mycobacterium bovis BCG at Two Growth Rates: Evidence for Growth Rate-Mediated Regulation of Ribosome Biosynthesis and Lipid Metabolism

Slow growth rate of mycobacteria

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