Pseudomonas aeruginosa Phenotypes Associated With Eradication Failure in Children With Cystic Fibrosis

Mayer-Hamblett, Nicole; Ramsey, Bonnie W.; Kulasekara, Hemantha D.; Wolter, Daniel J.; Houston, L. L.; Pope, Charles E.; Kulasekara, Bridget R.; Armbruster, Catherine R.; Burns, Jane L.; Retsch‐Bogart, George; Rosenfeld, Margaret; Gibson, Ronald L.; Miller, Samuel I.; Khan, Umer; Hoffman, Lucas R.

doi:10.1093/cid/ciu385

Cited by 66 publications

(66 citation statements)

References 42 publications

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“…The RSCV phenotype promotes biofilm formation and provides advantages for the bacterium, such as increased tolerance toward antibiotics and immune responses of the host (4-7). As a consequence, the appearance of RSCVs in clinical samples from infected tissues is often associated with poor patient outcome (8,9). The RSCV phenotype in P. aeruginosa is the result of increased production of exopolysaccharides and bacterial adhesins, which are central components of the biofilm matrix (10)(11)(12)(13)(14)(15).…”

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confidence: 99%

The Cyclic AMP-Vfr Signaling Pathway in Pseudomonas aeruginosa Is Inhibited by Cyclic Di-GMP

Almblad¹,

Harrison²,

Rybtke³

et al. 2015

J. Bacteriol.

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The opportunistic human pathogen Pseudomonas aeruginosa expresses numerous acute virulence factors in the initial phase of infection, and during long-term colonization it undergoes adaptations that optimize survival in the human host. Adaptive changes that often occur during chronic infection give rise to rugose small colony variants (RSCVs), which are hyper-biofilmforming mutants that commonly possess mutations that increase production of the biofilm-promoting secondary messenger cyclic di-GMP (c-di-GMP). We show that RSCVs display a decreased production of acute virulence factors as a direct result of elevated c-di-GMP content. Overproduction of c-di-GMP causes a decrease in the transcription of virulence factor genes that are regulated by the global virulence regulator Vfr. The low level of Vfr-dependent transcription is caused by a low level of its coactivator, cyclic AMP (cAMP), which is decreased in response to a high level of c-di-GMP. Mutations that cause reversion of the RSCV phenotype concomitantly reactivate Vfr-cAMP signaling. Attempts to uncover the mechanism underlying the observed c-di-GMP-mediated lowering of cAMP content provided evidence that it is not caused by inhibition of adenylate cyclase production or activity and that it is not caused by activation of cAMP phosphodiesterase activity. In addition to the studies of the RSCVs, we present evidence that the deeper layers of wild-type P. aeruginosa biofilms have high c-di-GMP levels and low cAMP levels. IMPORTANCEOur work suggests that cross talk between c-di-GMP and cAMP signaling pathways results in downregulation of acute virulence factors in P. aeruginosa biofilm infections. Knowledge about this cross-regulation adds to our understanding of virulence traits and immune evasion by P. aeruginosa in chronic infections and may provide new approaches to eradicate biofilm infections.

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confidence: 99%

The Cyclic AMP-Vfr Signaling Pathway in Pseudomonas aeruginosa Is Inhibited by Cyclic Di-GMP

Almblad¹,

Harrison²,

Rybtke³

et al. 2015

J. Bacteriol.

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“…However, these small studies, which each generally focused on one P. aeruginosa phenotype, were limited in their ability to describe the interrelatedness of multiple adaptive changes across the course of P. aeruginosa infection and their associations with clinical outcomes. For example, although mucoidy has been associated with failure of eradication by antibiotic treatment in small, focused studies (21), our subsequent comparative analysis of many P. aeruginosa phenotypes in a larger clinical population found other, more common P. aeruginosa phenotypes to be much more highly associated with this outcome (22). To rigorously define the natural history of P. aeruginosa phenotypic changes, and the relationship between these changes and disease progression, large longitudinal studies comparing multiple P. aeruginosa phenotypes are required (13).…”

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confidence: 94%

Pseudomonas aeruginosa In VitroPhenotypes Distinguish Cystic Fibrosis Infection Stages and Outcomes

Mayer-Hamblett

Rosenfeld

Gibson

et al. 2014

Am J Respir Crit Care Med

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108

101

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Rationale: Pseudomonas aeruginosa undergoes phenotypic changes during cystic fibrosis (CF) lung infection. Although mucoidy is traditionally associated with transition to chronic infection, we hypothesized that additional in vitro phenotypes correlate with this transition and contribute to disease.Objectives: To characterize the relationships between in vitro P. aeruginosa phenotypes, infection stage, and clinical outcomes.Methods: A total of 649 children with CF and newly identified P. aeruginosa were followed for a median 5.4 years during which a total of 2,594 P. aeruginosa isolates were collected. Twenty-six in vitro bacterial phenotypes were assessed among the isolates, including measures of motility, exoproduct production, colony morphology, growth, and metabolism.Measurements and Main Results: P. aeruginosa phenotypes present at the time of culture were associated with both stage of infection (new onset, intermittent, or chronic) and the primary clinical outcome, occurrence of a pulmonary exacerbation (PE) in the subsequent 2 years. Two in vitro P. aeruginosa phenotypes best distinguished infection stages: pyoverdine production (31% of new-onset cultures, 48% of intermittent, 69% of chronic) and reduced protease production (31%, 39%, and 65%, respectively). The best P. aeruginosa phenotypic predictors of subsequent occurrence of a PE were mucoidy (odds ratio, 1.75; 95% confidence interval, 1.19-2.57) and reduced twitching motility (odds ratio, 1.43; 95% confidence interval, 1.11-1.84). Conclusions:In this large epidemiologic study of CF P. aeruginosa adaptation, P. aeruginosa isolates exhibited two in vitro phenotypes that best distinguished early and later infection stages. Among the many phenotypes tested, mucoidy and reduced twitching best predicted subsequent PE. These phenotypes indicate potentially useful prognostic markers of transition to chronic infection and advancing lung disease.

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“…This in turn leads to increased production of the regulator molecule c-di-GMP and thereby increased production of biofilm matrix components, as well as a hyperadherent and autoaggregative phenotype (14,15). The occurrence of RSCVs has been correlated with increased risk of failure of antipseudomonal treatment (16).…”

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confidence: 99%

Importance of the Exopolysaccharide Matrix in Antimicrobial Tolerance of Pseudomonas aeruginosa Aggregates

Goltermann

Tolker‐Nielsen

2017

Antimicrob Agents Chemother

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Pseudomonas aeruginosa is an opportunistic pathogen that can infect the lungs of cystic fibrosis (CF) patients and persist in the form of antibiotic-tolerant aggregates in the mucus. It has recently been suggested that such aggregates are formed due to restricted bacterial motility independent of the production of extracellular matrix components, and that they do not rely on an extracellular matrix for antimicrobial tolerance. However, we show here that biofilm matrix overexpression, as displayed by various clinical isolates, significantly protects P. aeruginosa aggregates against antimicrobial treatment. Alginate-overproducing mucA mutant bacteria growing in aggregates showed highly increased antibiotic tolerance compared to wild-type bacteria in aggregates. Deletion of algD in the mucA mutant strain abrogated alginate production and reversed the antibiotic tolerance displayed by the aggregates to a level similar to that observed for aggregates formed by the wild type. The P. aeruginosa ΔwspF and ΔyfiR mutant strains both overproduce Pel and Psl exopolysaccharide, and when these bacteria grew in aggregates, they showed highly increased antibiotic tolerance compared to wild-type bacteria growing in aggregates. However, the ΔwspF and ΔyfiR mutant strains, deficient in Pel/Psl production due to additional ΔpelA ΔpslBCD deletions, formed aggregates that displayed antibiotic tolerance levels close to those of wild-type aggregates. These results suggest that biofilm matrix components, such as alginate, Pel, and Psl, do play a role in the tolerance toward antimicrobials when bacteria grow as aggregates.

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Pseudomonas aeruginosa Phenotypes Associated With Eradication Failure in Children With Cystic Fibrosis

Cited by 66 publications

References 42 publications

The Cyclic AMP-Vfr Signaling Pathway in Pseudomonas aeruginosa Is Inhibited by Cyclic Di-GMP

The Cyclic AMP-Vfr Signaling Pathway in Pseudomonas aeruginosa Is Inhibited by Cyclic Di-GMP

Pseudomonas aeruginosa In VitroPhenotypes Distinguish Cystic Fibrosis Infection Stages and Outcomes

Importance of the Exopolysaccharide Matrix in Antimicrobial Tolerance of Pseudomonas aeruginosa Aggregates

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