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Role of small colony variants in persistence of Pseudomonas aeruginosa infections in cystic fibrosis lungs.

Malone JG - Infect Drug Resist (2015)

Bottom Line: The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates.Here, we review the current state of research in clinical P. aeruginosa SCVs.We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment.

View Article: PubMed Central - PubMed

Affiliation: John Innes Centre, Norwich, UK ; School of Biological Sciences, University of East Anglia, Norwich, UK.

ABSTRACT
Pseudomonas aeruginosa is an opportunistic pathogen that predominates during the later stages of cystic fibrosis (CF) lung infections. Over many years of chronic lung colonization, P. aeruginosa undergoes extensive adaptation to the lung environment, evolving both toward a persistent, low virulence state and simultaneously diversifying to produce a number of phenotypically distinct morphs. These lung-adapted P. aeruginosa strains include the small colony variants (SCVs), small, autoaggregative isolates that show enhanced biofilm formation, strong attachment to surfaces, and increased production of exopolysaccharides. Their appearance in the sputum of CF patients correlates with increased resistance to antibiotics, poor lung function, and prolonged persistence of infection, increasing their relevance as a subject for clinical investigation. The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates. Here, we review the current state of research in clinical P. aeruginosa SCVs. We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment.

No MeSH data available.


Related in: MedlinePlus

Mutational routes to SCV formation.Notes: The diagram shows part of the cdG/RsmA signaling network in Pseudomonas aeruginosa. Hypothetical SCV-inducing mutations in uncharacterized DGCs are included. Signaling systems where mutations have been implicated in clinically relevant SCV formation are circled. Activating signals are denoted with arrows, suppression with bars. Purple hexagons represent cdG molecules. Pathways where the link to SCV is hypothetical or uncertain are marked with question marks (?). The dashed arrow refers to a pathway where the relationship to clinical SCV formation is currently unclear.Abbreviations: SCV, small colony variant; DGC, diguanylate cyclase.
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f5-idr-8-237: Mutational routes to SCV formation.Notes: The diagram shows part of the cdG/RsmA signaling network in Pseudomonas aeruginosa. Hypothetical SCV-inducing mutations in uncharacterized DGCs are included. Signaling systems where mutations have been implicated in clinically relevant SCV formation are circled. Activating signals are denoted with arrows, suppression with bars. Purple hexagons represent cdG molecules. Pathways where the link to SCV is hypothetical or uncertain are marked with question marks (?). The dashed arrow refers to a pathway where the relationship to clinical SCV formation is currently unclear.Abbreviations: SCV, small colony variant; DGC, diguanylate cyclase.

Mentions: Perhaps unsurprisingly, the most commonly identified SCV-inducing mutations are loss-of-function mutations in repressor proteins that control the activity of DGCs (Table 1). A well-studied example is the Wsp pathway,41 which contains a methyl-accepting chemotaxis receptor (WspA) and a DGC response regulator (WspR). WspR overproduction/activation induces an SCV phenotype,22,41 displaying strong attachment and increased expression of the pel and psl exopolysaccharide operons. Under laboratory conditions, the principle route to SCV evolution is via loss-of-function mutations in the methylesterase gene wspF.25,41 Without WspF, WspA and hence WspR are constitutively activated, leading to cdG synthesis and SCV formation through EPS overproduction (Figure 5).41,78 There is evidence that wspF loss-of-function also represents a route to clinical SCV evolution. In 2006, Smith et al6 carried out a longitudinal study of lung-adapted P. aeruginosa isolates and identified several different backgrounds in which the wspF gene was mutated. This study also identified a number of mutations in the transcriptional regulator fleQ. Deletion of fleQ induces an autoaggregative phenotype in PA01, with many of the characteristics of SCV colonies.54 While the morphologies of the lung isolates in the Smith et al6 study were not characterized in detail, these data nonetheless implicate both wspF and fleQ as potential mutagenic targets for SCV generation in the CF lung (Figure 5).


Role of small colony variants in persistence of Pseudomonas aeruginosa infections in cystic fibrosis lungs.

Malone JG - Infect Drug Resist (2015)

Mutational routes to SCV formation.Notes: The diagram shows part of the cdG/RsmA signaling network in Pseudomonas aeruginosa. Hypothetical SCV-inducing mutations in uncharacterized DGCs are included. Signaling systems where mutations have been implicated in clinically relevant SCV formation are circled. Activating signals are denoted with arrows, suppression with bars. Purple hexagons represent cdG molecules. Pathways where the link to SCV is hypothetical or uncertain are marked with question marks (?). The dashed arrow refers to a pathway where the relationship to clinical SCV formation is currently unclear.Abbreviations: SCV, small colony variant; DGC, diguanylate cyclase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524453&req=5

f5-idr-8-237: Mutational routes to SCV formation.Notes: The diagram shows part of the cdG/RsmA signaling network in Pseudomonas aeruginosa. Hypothetical SCV-inducing mutations in uncharacterized DGCs are included. Signaling systems where mutations have been implicated in clinically relevant SCV formation are circled. Activating signals are denoted with arrows, suppression with bars. Purple hexagons represent cdG molecules. Pathways where the link to SCV is hypothetical or uncertain are marked with question marks (?). The dashed arrow refers to a pathway where the relationship to clinical SCV formation is currently unclear.Abbreviations: SCV, small colony variant; DGC, diguanylate cyclase.
Mentions: Perhaps unsurprisingly, the most commonly identified SCV-inducing mutations are loss-of-function mutations in repressor proteins that control the activity of DGCs (Table 1). A well-studied example is the Wsp pathway,41 which contains a methyl-accepting chemotaxis receptor (WspA) and a DGC response regulator (WspR). WspR overproduction/activation induces an SCV phenotype,22,41 displaying strong attachment and increased expression of the pel and psl exopolysaccharide operons. Under laboratory conditions, the principle route to SCV evolution is via loss-of-function mutations in the methylesterase gene wspF.25,41 Without WspF, WspA and hence WspR are constitutively activated, leading to cdG synthesis and SCV formation through EPS overproduction (Figure 5).41,78 There is evidence that wspF loss-of-function also represents a route to clinical SCV evolution. In 2006, Smith et al6 carried out a longitudinal study of lung-adapted P. aeruginosa isolates and identified several different backgrounds in which the wspF gene was mutated. This study also identified a number of mutations in the transcriptional regulator fleQ. Deletion of fleQ induces an autoaggregative phenotype in PA01, with many of the characteristics of SCV colonies.54 While the morphologies of the lung isolates in the Smith et al6 study were not characterized in detail, these data nonetheless implicate both wspF and fleQ as potential mutagenic targets for SCV generation in the CF lung (Figure 5).

Bottom Line: The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates.Here, we review the current state of research in clinical P. aeruginosa SCVs.We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment.

View Article: PubMed Central - PubMed

Affiliation: John Innes Centre, Norwich, UK ; School of Biological Sciences, University of East Anglia, Norwich, UK.

ABSTRACT
Pseudomonas aeruginosa is an opportunistic pathogen that predominates during the later stages of cystic fibrosis (CF) lung infections. Over many years of chronic lung colonization, P. aeruginosa undergoes extensive adaptation to the lung environment, evolving both toward a persistent, low virulence state and simultaneously diversifying to produce a number of phenotypically distinct morphs. These lung-adapted P. aeruginosa strains include the small colony variants (SCVs), small, autoaggregative isolates that show enhanced biofilm formation, strong attachment to surfaces, and increased production of exopolysaccharides. Their appearance in the sputum of CF patients correlates with increased resistance to antibiotics, poor lung function, and prolonged persistence of infection, increasing their relevance as a subject for clinical investigation. The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates. Here, we review the current state of research in clinical P. aeruginosa SCVs. We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment.

No MeSH data available.


Related in: MedlinePlus