Persistence: mechanisms for triggering and enhancing phenotypic variability

Balaban, Nathalie Q.

doi:10.1016/j.gde.2011.10.001

Cited by 137 publications

(129 citation statements)

References 71 publications

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“…acteria commonly utilize phenotypic variation (also known as clonal variation) to adapt at the community level to rapid changes in environment, such as those that may be encountered by pathogens during host colonization (1)(2)(3). Broadly defined, phenotypic variation occurs when an isogenic population exhibits two or more distinct phenotypes.…”

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confidence: 99%

“…cecropin-6 transcript levels were measured and normalized against rpS3 using the following primers: cecropin-6 F (5=-GGT CAAAGGATTCGTGACGC-3=) and cecropin-6 R (5=-TTTGATTGTCC TTTGAAAATGGCG-3=) and rpS3 F (5=-ACTTCTCAGGCAAGGAGTG C-3=) and rpS3 R (5=-GTCACCAGGATGTGGTCTGG-3=). Data were normalized using the formula 2 Cq(rpS3) [2][3][4][5][6] and are presented as a ratio of infected versus PBS-injected larvae, where C q represents the quantification cycle.…”

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confidence: 99%

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The Global Transcription Factor Lrp Controls Virulence Modulation in Xenorhabdus nematophila

2015

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The bacterium Xenorhabdus nematophila engages in phenotypic variation with respect to pathogenicity against insect larvae, yielding both virulent and attenuated subpopulations of cells from an isogenic culture. The global regulatory protein Lrp is necessary for X. nematophila virulence and immunosuppression in insects, as well as colonization of the mutualistic host nematode Steinernema carpocapsae, and mediates expression of numerous genes implicated in each of these phenotypes. Given the central role of Lrp in X. nematophila host associations, as well as its involvement in regulating phenotypic variation pathways in other bacteria, we assessed its function in virulence modulation. We discovered that expression of lrp varies within an isogenic population, in a manner that correlates with modulation of virulence. Unexpectedly, although Lrp is necessary for optimal virulence and immunosuppression, cells expressing high levels of lrp were attenuated in these processes relative to those with low to intermediate lrp expression. Furthermore, fixed expression of lrp at high and low levels resulted in attenuated and normal virulence and immunosuppression, respectively, and eliminated population variability of these phenotypes. These data suggest that fluctuating lrp expression levels are sufficient to drive phenotypic variation in X. nematophila. IMPORTANCEMany bacteria use cell-to-cell phenotypic variation, characterized by distinct phenotypic subpopulations within an isogenic population, to cope with environmental change. Pathogenic bacteria utilize this strategy to vary antigen or virulence factor expression. Our work establishes that the global transcription factor Lrp regulates phenotypic variation in the insect pathogen Xenorhabdus nematophila, leading to attenuation of virulence and immunosuppression in insect hosts. Unexpectedly, we found an inverse correlation between Lrp expression levels and virulence: high levels of expression of Lrp-dependent putative virulence genes are detrimental for virulence but may have an adaptive advantage in other aspects of the life cycle. Investigation of X. nematophila phenotypic variation facilitates dissection of this phenomenon in the context of a naturally occurring symbiosis.

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The Global Transcription Factor Lrp Controls Virulence Modulation in Xenorhabdus nematophila

2015

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“…As such, SCVs have high rates of reversion to the NCP, which is strongly selected for in vitro due to the increased growth rate of NCP S. aureus on laboratory media (24,30,35). It is also possible that some SCVs might be the product of phenotypic heterogeneity (persisters [2,3]); however, there is currently no evidence for this, and persister bacteria do not usually replicate.…”

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Phenotype Switching Is a Natural Consequence of Staphylococcus aureus Replication

Edwards

2012

J Bacteriol

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The pathogen Staphylococcus aureus undergoes phenotype switching in vivo from its normal colony phenotype (NCP) to a slowgrowing, antibiotic-resistant small-colony-variant (SCV) phenotype that is associated with persistence in host cells and tissues. However, it is not clear whether phenotype switching is the result of a constitutive process that is selected for under certain conditions or is triggered by particular environmental stimuli. Examination of cultures of diverse S. aureus strains in the absence of selective pressure consistently revealed a small gentamicin-resistant SCV subpopulation that emerged during exponential-phase NCP growth and increased in number until NCP stationary phase. Treatment of replicating bacteria with the antibiotic gentamicin, which inhibited NCP but not SCV replication, resulted in an initial decrease in SCV numbers, demonstrating that SCVs arise as a consequence of NCP replication. However, SCV population expansion in the presence of gentamicin was reestablished by selection of phenotype-stable SCVs and subsequent SCV replication. In the absence of selective pressure, however, phenotype switching was bidirectional and occurred at a high frequency during NCP replication, resulting in SCV turnover. In summary, these data demonstrate that S. aureus phenotype switching occurs via a constitutive mechanism that generates a dynamic, antibiotic-resistant subpopulation of bacteria that can revert to the parental phenotype. The emergence of SCVs can therefore be considered a normal part of the S. aureus life cycle and provides an insurance policy against exposure to antibiotics that would otherwise eliminate the entire population.

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“…He identified a very small subpopulation in a Staphylococcus aureus culture which survived prolonged exposure to bactericidal concentrations of penicillin. Upon recultivation of this subpopulation and another round of antibiotic exposure, an equal proportion of bacilli survived, indicating that survival was not due to genetically inherited antibiotic resistance [362]. Persistence has been shown in all bacteria tested for it, and there are two types of persistence: Type 1 persistence requires a triggering signal such as starvation, biofilm formation, quorum sensing, exposure to the host immune system or to antibiotics, and this can be genetically encoded, for example by toxin-antitoxin systems [362].…”

Section: Mechanisms and Models For Mtb Dormancy And Persistencementioning

confidence: 96%

“…Upon recultivation of this subpopulation and another round of antibiotic exposure, an equal proportion of bacilli survived, indicating that survival was not due to genetically inherited antibiotic resistance [362]. Persistence has been shown in all bacteria tested for it, and there are two types of persistence: Type 1 persistence requires a triggering signal such as starvation, biofilm formation, quorum sensing, exposure to the host immune system or to antibiotics, and this can be genetically encoded, for example by toxin-antitoxin systems [362]. Type 1 persistence is further characterized by slowed or arrested growth (the classical definition of dormancy), and in a stationary phase-culture of Escherichia coli, growth-arrested but not dividing bacteria survived a subsequent ampicillin shock [363].…”

Section: Mechanisms and Models For Mtb Dormancy And Persistencementioning

confidence: 96%

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

Raffetseder¹

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Persistence: mechanisms for triggering and enhancing phenotypic variability

Cited by 137 publications

References 71 publications

The Global Transcription Factor Lrp Controls Virulence Modulation in Xenorhabdus nematophila

The Global Transcription Factor Lrp Controls Virulence Modulation in Xenorhabdus nematophila

Phenotype Switching Is a Natural Consequence of Staphylococcus aureus Replication

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

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