Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis

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Pseudomonas aeruginosa is an opportunistic pathogen that significantly contributes to morbidity and mortality in patients with cystic fibrosis. Defective mucociliary clearance associated with the absence of the functional cystic fibrosis transmembrane conductance regulator in airway epithelium plays a critical role in the initial colonization of this pathogen. P. aeruginosa, while initiating a profound inflammatory response, employs multiple mechanisms to evade immune clearance. The capacity to grow in biofilms and the selection of mutants with a mucoid phenotype are major adaptations that allow its persistence in the airways.

Introduction

The upper airways represent a primary site for the introduction and deposition of potential pathogenic microorganisms through inspired air. The ciliated epithelium that lines the airways possesses several mechanisms to prevent colonization by inhaled bacteria, thus the lower respiratory tract usually remains sterile. Under certain circumstances, however, when normal clearance mechanisms are impaired, bacteria can colonize and cause lung disease. Pseudomonas aeruginosa is an opportunistic pathogen that causes pneumonia in individuals whose natural lung defences are compromised, and it is known to significantly contribute to the pathogenesis of cystic fibrosis (CF). In CF, defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelium and submucosal glands is associated with chronic disease of the respiratory tract, manifested even early in life by airway obstruction and recurrent infections of the lung and paranasal sinuses. The CF lung is particularly susceptible to P. aeruginosa infection, and this organism plays a critical role in the development and progression of pulmonary disease in these patients [1]. Indeed, chronic airway inflammation with recurrent P. aeruginosa infection is the major cause of morbidity and mortality in CF patients [2]. Perhaps the most important feature of P. aeruginosa is its ability to persist in the CF lung as a result of its tremendous genetic flexibility. Environmental isolates that colonize the airways are motile and express numerous exoproducts (e.g. protease, phospholipases and elastase). The organisms rapidly switch to a more indolent mode of growth, turning off the expression of immunostimulatory products such as flagella and initiating its biofilm mode of growth; this adaptation plays a critical role during chronic infection with P. aeruginosa. This review focuses on the underlining conditions that predispose the CF lung to P. aeruginosa colonization, infection and persistence. Interactions between P. aeruginosa and the airway epithelium that lead to exacerbated lung inflammation and persistence are also discussed.

Section snippets

Mucociliary clearance

In the normal lung, an airway surface liquid (ASL) lining together with beating cilia helps to remove microbes and particles that enter the airways, a process that it is compromised in CF (Figure 1). The airway surface fluid itself has anti-microbial activity owing to a large array of molecules secreted by airway cells in response to bacterial challenge, such as antimicrobial peptides, lysozyme and lactoferrin. The depth of ASL is normally controlled by a balance between the opposing processes

P. aeruginosa interactions with the airway epithelium

Whether CF airway epithelial cells exhibit exaggerated inflammation in response to chronic bacterial stimulation or, alternatively, because the epithelia have an inherent defect predisposing to a hyperinflammatory state, or even both, has been widely debated. In vitro studies using cell lines and primary airway cells suggest that dysfunctional CFTR by itself can increase the activity of pro-inflammatory transcription factors such as nuclear factor-κB [27, 28, 29, 30]. Similar results were

Pseudomonas persistence in the cystic fibrosis lung

P. aeruginosa has enormous genetic and metabolic flexibility that allows it to adapt to the milieu and persist within the airways of CF patients (Figure 1). The genotypes and phenotypes of the strains present in late stages of the disease differ substantially from those that initially colonize the lungs [52]. The organisms associated with the initial colonization and infection of the CF lung phenotypically reflect the isolates in the environment, which are motile and express several

Conclusions

The airways of CF patients, with altered innate defense mechanisms, provide a niche for P. aeruginosa colonization and infection. Current CF therapies attempt to provide nutritional support, improve mucociliary clearance, decrease inflammation and eradicate bacterial pathogens by the use of antibiotics [72]. Whereas a long-term therapeutic goal is to address the underlying ion transport defect found in CF airways, a feasible approach in the future would be to target bacteria to prevent chronic

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was funded by the NHI grants RO1DK39693, RO1HL073989 and RO1HL079395 to Alice Prince. Marisa Gómez was funded by a US Cystic Fibrosis Foundation postdoctoral fellowship.

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