Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes

Limoli, Dominique H.; Yang, Juan; Khansaheb, Monal; Helfman, B.; Peng, Limin; Stecenko, Arlene A.; Goldberg, Joanna B.

doi:10.1007/s10096-016-2621-0

Cited by 136 publications

(132 citation statements)

References 28 publications

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“…We observed that coinfection correlated with poor patient outcome, including a decline in lung function, compared to monoinfected patients (17). To investigate if there are differences in the isolates from these patients that may contribute to establishing coinfection, we obtained 28 P. aeruginosa strains and 20 S. aureus strains from patients who were either coinfected or monoinfected from the CF Biospecimen Registry (CFBR) at Emory+Children's Center for Cystic Fibrosis and Airways Disease Research.…”

Section: Resultsmentioning

confidence: 76%

“…We and others have observed a correlation between coinfection and poor patient outcome, whereby infection with both P. aeruginosa and S. aureus correlates with increased pulmonary exacerbations and lower baseline forced expiratory volumes of the lung in 1 s (FEV 1 ) compared to patients who were monoinfected with only S. aureus or P. aeruginosa (17–19). Examination of 234 CF patients at Emory+Children's Center for Cystic Fibrosis and Airways Disease Research revealed that 73 patients (31%) were coinfected with P. aeruginosa and S. aureus (17). Moreover, recent data demonstrate higher rates of infection with S. aureus in patients later in life than previously appreciated (20).…”

Section: Introductionmentioning

confidence: 95%

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

Limoli

Whitfield

Kitao

et al. 2017

mBio

133

186

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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: Resultsmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 95%

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

Limoli

Whitfield

Kitao

et al. 2017

mBio

133

186

View full text Add to dashboard Cite

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“…S. aureus is the most prevalent pathogen in younger patients with CF, while P. aeruginosa is highly prevalent in adult patients (9, 10). The presence of both P. aeruginosa and S. aureus is associated with decreased lung function, as measured by forced expiratory volume in 1 s (FEV 1 ), and poor patient outcomes (11–14). …”

Section: Introductionmentioning

confidence: 99%

Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection

Orazi

O’Toole

2017

mBio

159

177

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The airways of cystic fibrosis (CF) patients have thick mucus, which fosters chronic, polymicrobial infections. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients. In this study, we tested whether P. aeruginosa influences the susceptibility of S. aureus to frontline antibiotics used to treat CF lung infections. Using our in vitro coculture model, we observed that addition of P. aeruginosa supernatants to S. aureus biofilms grown either on epithelial cells or on plastic significantly decreased the susceptibility of S. aureus to vancomycin. Mutant analyses showed that 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), a component of the P. aeruginosa Pseudomonas quinolone signal (PQS) system, protects S. aureus from the antimicrobial activity of vancomycin. Similarly, the siderophores pyoverdine and pyochelin also contribute to the ability of P. aeruginosa to protect S. aureus from vancomycin, as did growth under anoxia. Under our experimental conditions, HQNO, P. aeruginosa supernatant, and growth under anoxia decreased S. aureus growth, likely explaining why this cell wall-targeting antibiotic is less effective. P. aeruginosa supernatant did not confer additional protection to slow-growing S. aureus small colony variants. Importantly, P. aeruginosa supernatant protects S. aureus from other inhibitors of cell wall synthesis as well as protein synthesis-targeting antibiotics in an HQNO- and siderophore-dependent manner. We propose a model whereby P. aeruginosa causes S. aureus to shift to fermentative growth when these organisms are grown in coculture, leading to reduction in S. aureus growth and decreased susceptibility to antibiotics targeting cell wall and protein synthesis.

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“…In the CF lung, there is an age‐dependent progression of different types of chronic bacterial infections, starting with Staphylococcus aureus , and Haemophilus influenza , and progressing to Pseudomonas aeruginosa (controlled by intermittent tobramycin ® ) and finally Berkholderia cenocepacia complex . The Cystic Fibrosis Foundation has also compiled detailed records on infection incidence in the entire US population.…”

Section: What Symptoms Must Be Suppressed By a Durable Therapy In Thementioning

confidence: 99%

Induced pluripotent stem cells for treating cystic fibrosis: State of the science

Pollard¹,

Pollard

2018

Pediatric Pulmonology

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Induced pluripotent stem cells (iPSCs) are a recently developed technology in which fully differentiated cells such as fibroblasts from individual CF patients can be repaired with [wildtype] CFTR, and reprogrammed to differentiate into fully differentiated cells characteristic of the proximal and distal airways. Here, we review properties of different epithelial cells in the airway, and the in vitro genetic roadmap which iPSCs follow as they are step-wise differentiated into either basal stem cells, for the proximal airway, or into Type II Alveolar cells for the distal airways. The central theme is that iPSC-derived basal stem cells, are penultimately dependent on NOTCH signaling for differentiation into club cells, goblet cells, ciliated cells, and neuroendocrine cells. Furthermore, given the proper matrix, these cellular progenies are also able to self-assemble into a fully functional pseudostratified squamous proximal airway epithelium. By contrast, club cells are reserve stem cells which are able to either differentiate into goblet or ciliated cells, but also to de-differentiate into basal stem cells. Variant club cells, located at the transition between airway and alveoli, may also be responsible for differentiation into Type II Alveolar cells, which then differentiate into Type I Alveolar cells for gas exchange in the distal airway. Using gene editing, the mutant CFTR gene in iPSCs from CF patients can be repaired, and fully functional epithelial cells can thus be generated through directed differentiation. However, there is a limitation in that the lung has other CFTR-dependent cells besides epithelial cells. Another limitation is that there are CFTR-dependent cells in other organs which would continue to contribute to CF disease. Furthermore, there are also bystander or modifier genes which affect disease outcome, not only in the lung, but specifically in other CF-affected organs. Finally, we discuss future personalized applications of the iPSC technology, many of which have already survived the "proof-of-principle" test. These include (i) patient-derived iPSCs used as a "lung-on-a-chip" tool for personalized drug discovery; (ii) replacement of mutant lung cells by wildtype lung cells in the living lung; and (iii) development of bio-artificial lungs. It is hoped that this review will give the reader a roadmap through the most complicated of the obstacles, and foster a guardedly optimistic view of how some of the remaining obstacles might one day be overcome.

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Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes

Cited by 136 publications

References 28 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

Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection

Induced pluripotent stem cells for treating cystic fibrosis: State of the science

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