Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression

Hoffman, Lucas R.; Kulasekara, Hemantha D.; Emerson, Julia; Houston, L. L.; Burns, Jane L.; Ramsey, Bonnie W.; Miller, Samuel I.

doi:10.1016/j.jcf.2008.09.006

Cited by 274 publications

(307 citation statements)

References 22 publications

(44 reference statements)

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“…Recent reports revealed that a considerable proportion of P. aeruginosa isolates from CF patients possess mutations in the lasR gene (12,19). Being contradictory to the current view that the lasR-mediated QS system is essential for P. aeruginosa virulence, these findings suggest that (i) QS in the CF airway may not be required for bacterial survival, especially at the chronic stage, and (ii) QS regulation may occur differently under conditions with reduced oxygen tension.…”

mentioning

confidence: 79%

“…However, recent genetic studies using diverse P. aeruginosa clinical isolates reported that adaptive mutations in the lasR gene occur spontaneously in the course of chronic airway infection in CF (9,12,19,42). Phenotype on April 7, 2019 by guest http://iai.asm.org/ changes conferred on P. aeruginosa by these mutations include (i) facilitated growth on amino acids present in relatively large quantities in CF airways (1,12), (ii) an efficient shift to an anaerobic mode of growth using nitrate over oxygen (20), and (iii) elevated antibiotic resistance (12,20).…”

Section: Discussionmentioning

confidence: 99%

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Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

et al. 2011

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Pseudomonas aeruginosa, an opportunistic pathogen of clinical importance, causes chronic airway infections in patients with cystic fibrosis (CF). Current literature suggests that pockets with reduced oxygen tension exist in the CF airway mucus. However, virulence features of this opportunistic pathogen under such conditions are largely unknown. Cell-free supernatant of the standard laboratory P. aeruginosa strain PAO1 obtained from anaerobic culture, but not aerobic culture, failed to kill A549 human airway epithelial cells. Further investigation revealed that this reduced cytotoxicity upon anaerobiosis was due to the suppressed secretion of elastase, a virulence factor controlled by P. aeruginosa quorum sensing (QS). Both a lacZ-reporter fusion assay and quantitative real-time PCR (RT-PCR) analysis demonstrated that transcription of the elastase-encoding lasB gene was substantially decreased during anaerobic growth compared with aerobic growth. Moreover, transcription of other genes controlled by the LasI/R QS system, such as rhlR, vqsR, mvfR, and rsaL, was also repressed under the same anaerobic growth conditions. Importantly, synthesis of 3-oxo-C 12 -HSL (PAI-1), an autoinducer molecule that mediates induction of the LasI/R QS system, was >22-fold decreased during anaerobic growth while C 4 -HSL (PAI-2), which mediates RhlI/R QS, was nondetectable under the same growth conditions. Transcription of the lasB gene was restored by exogenous supplementation with autoinducers, with PAI-2 more effective than PAI-1 or Pseudomonas quinolone signal (PQS) at restoring transcription of the lasB gene. Together, these results suggest that anaerobiosis deprives P. aeruginosa of the ability to regulate its virulence via QS and this misregulation attenuates the pathogenic potential of this important pathogen.

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confidence: 79%

Section: Discussionmentioning

confidence: 99%

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

et al. 2011

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“…An intriguing finding was mutations in mucA and lasR and the isolation of SCVs, as these genetic changes are known to promote disease progression in relation to chronic lung infection (Deretic et al, 1995;Haussler et al, 1999;Parad et al, 1999;Hoffman et al, 2009). To determine the frequency of these mutants in the sinuses, we screened the phenotypes of all sinus morphotypes isolated in the additional patients (Table 4).…”

Section: Sinus Isolates With Increased Antibiotic Resistance From Patmentioning

confidence: 99%

“…In addition, the initial infecting strains of P. aeruginosa often diversify into subpopulations with distinct colony morphologies (Wahba and Darrell, 1965;Thomassen et al, 1979). Major selective factors in the CF airways are believed to be the host immune system, nutrient composition and antibiotic treatments, and consequential adaptive changes of the bacterial phenotypes can seriously affect disease outcome and progression (Deretic et al, 1995;Haussler et al, 1999;Parad et al, 1999;Hoffman et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection

et al. 2011

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The opportunistic pathogen Pseudomonas aeruginosa is a frequent colonizer of the airways of patients suffering from cystic fibrosis (CF). Depending on early treatment regimens, the colonization will, with high probability, develop into chronic infections sooner or later, and it is important to establish under which conditions the switch to chronic infection takes place. In association with a recently established sinus surgery treatment program for CF patients at the Copenhagen CF Center, colonization of the paranasal sinuses with P. aeruginosa has been investigated, paralleled by sampling of sputum from the same patients. On the basis of genotyping and phenotypic characterization including transcription profiling, the diversity of the P. aeruginosa populations in the sinuses and the lower airways was investigated and compared. The observations made from several children show that the paranasal sinuses constitute an important niche for the colonizing bacteria in many patients. The paranasal sinuses often harbor distinct bacterial subpopulations, and in the early colonization phases there seems to be a migration from the sinuses to the lower airways, suggesting that independent adaptation and evolution take place in the sinuses. Importantly, before the onset of chronic lung infection, lineages with mutations conferring a large fitness benefit in CF airways such as mucA and lasR as well as small colony variants and antibiotic-resistant clones are part of the sinus populations. Thus, the paranasal sinuses potentially constitute a protected niche of adapted clones of P. aeruginosa, which can intermittently seed the lungs and pave the way for subsequent chronic lung infections.

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“…As early as 9 days post colonization in acutely ill patients, subpopulations of clinical Pa isolates defective in QS emerged with mutations in the autoinducer lasR (Kohler et al, 2009;Winstanley & Fothergill, 2009). QS-deficient lasR mutants have been detected in a significant proportion (30-63%) of CF Pa isolates (Feliziani et al, 2010;Hoffman et al, 2009). Moreover, isolates of Pa defective in lasR, lasI, and/or rhlI have been shown to be much less virulent than QS-positive strains in animal models (Willcox et al, 2008;Wu et al, 2001).…”

Section: Accumulation Of Quorum Sensing Deficient Pa Reflects Developmentioning

confidence: 99%

Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution

Qin

2014

Critical Reviews in Microbiology

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To cite this article: Xuan Qin (2016) Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution, Critical Reviews in Microbiology, 42:1, 144-157, DOI: 10.3109/1040841X.2014 AbstractGain of ''antimicrobial resistance'' and ''adaptive virulence'' has been the dominant view of Pseudomonas aeruginosa (Pa) in cystic fibrosis (CF) in the progressively damaged host airway over the course of this chronic infection. However, the pathogenic effects of CF airway-adapted Pa strains are notably reduced. We propose that CF Pa and other bacterial cohabitants undergo host adaptation which resembles the changes found in bacterial symbionts in animal hosts. Development of clonally selected and intraspecific isogenic Pa strains which display divergent colony morphology, growth rate, auxotrophy, and antibiotic susceptibility in vitro suggests an adaptive sequence of infective exploitation-parasitism-symbiotic evolution driven by host defenses. Most importantly, the emergence of CF pseudomonal auxotrophy is frequently associated with a few specific amino acids. The selective retention or loss of specific amino acid biosynthesis in CF-adapted Pa reflects bacterium-host symbiosis and coevolution during chronic infection, not nutrient availability. This principle also argues against the long-standing concept of dietary availability leading to evolution of essential amino acid requirements in humans. A novel model of pseudomonal adaptation through multicellular bacterial syntrophy is proposed to explain early events in bacterial gene decay and decreased (not increased) virulence due to symbiotic response to host defense.

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Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression

Cited by 274 publications

References 22 publications

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection

Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution

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