The Approach to Pseudomonas aeruginosa in Cystic Fibrosis

Talwalkar, Jaideep S.; Murray, Thomas S.

doi:10.1016/j.ccm.2015.10.004

Cited by 67 publications

(61 citation statements)

References 81 publications

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“…Both S. aureus and P. aeruginosa exhibit intrinsic and acquired antibiotic resistance, making these infections difficult to treat (3, 4). S. aureus is among one of the earliest pathogens to infect pediatric CF patients, whereas P. aeruginosa infections are intermittent early on until a dominant clone emerges and P. aeruginosa becomes the predominant pathogen later in life (5). This inverse pattern of infection has led many investigators to speculate that P. aeruginosa eliminates S. aureus during infection—perhaps outcompeting S. aureus for limited nutrients in the lung and/or producing antimicrobial factors to kill S. aureus directly (recently reviewed in reference 6).…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosa Alginate Overproduction Promotes Coexistence with Staphylococcus aureus in a Model of Cystic Fibrosis Respiratory Infection

Limoli

Whitfield

Kitao

et al. 2017

mBio

142

193

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While complex intra- and interspecies microbial community dynamics are apparent during chronic infections and likely alter patient health outcomes, our understanding of these interactions is currently limited. For example, Pseudomonas aeruginosa and Staphylococcus aureus are often found to coinfect the lungs of patients with cystic fibrosis (CF), yet these organisms compete under laboratory conditions. Recent observations that coinfection correlates with decreased health outcomes necessitate we develop a greater understanding of these interbacterial interactions. In this study, we tested the hypothesis that P. aeruginosa and/or S. aureus adopts phenotypes that allow coexistence during infection. We compared competitive interactions of P. aeruginosa and S. aureus isolates from mono- or coinfected CF patients employing in vitro coculture models. P. aeruginosa isolates from monoinfected patients were more competitive toward S. aureus than P. aeruginosa isolates from coinfected patients. We also observed that the least competitive P. aeruginosa isolates possessed a mucoid phenotype. Mucoidy occurs upon constitutive activation of the sigma factor AlgT/U, which regulates synthesis of the polysaccharide alginate and dozens of other secreted factors, including some previously described to kill S. aureus. Here, we show that production of alginate in mucoid strains is sufficient to inhibit anti-S. aureus activity independent of activation of the AlgT regulon. Alginate reduces production of siderophores, 2-heptyl-4-hydroxyquinolone-N-oxide (HQNO), and rhamnolipids—each required for efficient killing of S. aureus. These studies demonstrate alginate overproduction may be an important factor driving P. aeruginosa coinfection with S. aureus.

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Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosa Alginate Overproduction Promotes Coexistence with Staphylococcus aureus in a Model of Cystic Fibrosis Respiratory Infection

Limoli

Whitfield

Kitao

et al. 2017

mBio

142

193

View full text Add to dashboard Cite

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“…The basic defect in CF predisposes to viral and bacterial airway infections (2). The most prevalent airway pathogen in adolescents and adults with CF is Pseudomonas aeruginosa (3,4). The chronic airway colonization with P. aeruginosa has been associated with a rapid decline in lung function, heightened lung inflammation, and worse prognosis (1).…”

mentioning

confidence: 99%

“…Antipseudomonal chemotherapy in CF comprises intravenous combination therapy with ␤-lactam antibiotics and aminoglycosides, oral fluoroquinolones, immunomodulatory treatment with azithromycin and aerosolized antibiotics such as tobramycin, aztreonam, or colistin (4)(5)(6)(7)(8). The high antimicrobial pressure exerted on the microorganism, which can persist and diversify in the patient's airways for decades, drives the emergence of drug resistance phenotypes (9,10).…”

mentioning

confidence: 99%

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Greipel

Fischer

Klockgether

et al. 2016

Antimicrob Agents Chemother

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bThe chronic airway infections with Pseudomonas aeruginosa in people with cystic fibrosis (CF) are treated with aerosolized antibiotics, oral fluoroquinolones, and/or intravenous combination therapy with aminoglycosides and ␤-lactam antibiotics. An international strain collection of 361 P. aeruginosa isolates from 258 CF patients seen at 30 CF clinics was examined for mutations in 17 antimicrobial susceptibility and resistance loci that had been identified as hot spots of mutation by genome sequencing of serial isolates from a single CF clinic. Combinatorial amplicon sequencing of pooled PCR products identified 1,112 sequence variants that were not present in the genomes of representative strains of the 20 most common clones of the global P. aeruginosa population. A high frequency of singular coding variants was seen in spuE, mexA, gyrA, rpoB, fusA1, mexZ, mexY, oprD, ampD, parR, parS, and envZ (amgS), reflecting the pressure upon P. aeruginosa in lungs of CF patients to generate novel protein variants. The proportion of nonneutral amino acid exchanges was high. Of the 17 loci, mexA, mexZ, and pagL were most frequently affected by independent stop mutations. Private and de novo mutations seem to play a pivotal role in the response of P. aeruginosa populations to the antimicrobial load and the individual CF host. C ystic fibrosis (CF) is a severe autosomal recessive trait that is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) (1). CFTR dysfunction affects many organs, but lung disease is responsible for the vast majority of morbidity and mortality in people with CF. The basic defect in CF predisposes to viral and bacterial airway infections (2). The most prevalent airway pathogen in adolescents and adults with CF is Pseudomonas aeruginosa (3, 4). The chronic airway colonization with P. aeruginosa has been associated with a rapid decline in lung function, heightened lung inflammation, and worse prognosis (1).Antipseudomonal chemotherapy in CF comprises intravenous combination therapy with ␤-lactam antibiotics and aminoglycosides, oral fluoroquinolones, immunomodulatory treatment with azithromycin and aerosolized antibiotics such as tobramycin, aztreonam, or colistin (4-8). The high antimicrobial pressure exerted on the microorganism, which can persist and diversify in the patient's airways for decades, drives the emergence of drug resistance phenotypes (9, 10). Typical targets are elements of replication, transcription, and translation, the cell wall, and transport and its regulation (9-11).During ongoing studies on the long-term microevolution of P. aeruginosa in lungs of 12 CF patients, we have identified 17 loci to be repetitively hit by mutations. These loci are known from the literature to be associated with the emergence of drug resistance in P. aeruginosa (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Hence, we became interested to know if and to what extent the global P. aeruginosa population in lungs of patients (CF lungs) carries mutations in these ge...

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“…These trends could be partially due to aggressive, early strategies to eradicate P. aeruginosa and more sensitive methods to detect Gram-positive microorganisms. Chronic P. aeruginosa infection has been linked to more rapid progression of lung disease and mortality in CF [30,31,32]. P. aeruginosa infects CF patients early in life and becomes a persistent pathogen in subsequent years [33].…”

Section: Antimicrobial Mechanisms Of Neutrophils Against Pseudomonmentioning

confidence: 99%

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

Rada

2017

Pathogens

102

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Cystic fibrosis (CF) affects 70,000 patients worldwide. Morbidity and mortality in CF is largely caused by lung complications due to the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. Cystic fibrosis airway inflammation is mediated by robust infiltration of polymorphonuclear neutrophil granulocytes (PMNs, neutrophils). Neutrophils are not capable of clearing lung infections and contribute to tissue damage by releasing their dangerous cargo. Pseudomonas aeruginosa is an opportunistic pathogen causing infections in immunocompromised individuals. P. aeruginosa is a main respiratory pathogen in CF infecting most patients. Although PMNs are key to attack and clear P. aeruginosa in immunocompetent individuals, PMNs fail to do so in CF. Understanding why neutrophils cannot clear P. aeruginosa in CF is essential to design novel therapies. This review provides an overview of the antimicrobial mechanisms by which PMNs attack and eliminate P. aeruginosa. It also summarizes current advances in our understanding of why PMNs are incapable of clearing P. aeruginosa and how this bacterium adapts to and resists PMN-mediated killing in the airways of CF patients chronically infected with P. aeruginosa.

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The Approach to Pseudomonas aeruginosa in Cystic Fibrosis

Cited by 67 publications

References 81 publications

Pseudomonas aeruginosa Alginate Overproduction Promotes Coexistence with Staphylococcus aureus in a Model of Cystic Fibrosis Respiratory Infection

Pseudomonas aeruginosa Alginate Overproduction Promotes Coexistence with Staphylococcus aureus in a Model of Cystic Fibrosis Respiratory Infection

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

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