Review
CFTR mutations and host susceptibility to Pseudomonas aeruginosa lung infection

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Abstract

The susceptibility of cystic fibrosis patients to bacterial pathogens is associated with deficient airway antimicrobial peptide activity, and airway-surface-liquid dehydration with decreased transport velocity and hypersecretion of mucus. Susceptibility to Pseudomonas aeruginosa infection has been linked to the role of the cystic fibrosis transmembrane conductance regulator protein as a receptor for P. aeruginosa. Binding of P. aeruginosa coordinates lung clearance as part of innate immunity. The function of CFTR in innate immunity to P. aeruginosa infection is multifactorial, with one key component being a specific ligand–receptor interaction between the protein and the microbe.

Introduction

Experiments of nature leading to an increased frequency of a pathologic state associated with a specific genotype are very useful for unraveling the molecular and cellular bases for susceptibility and progression of the pathologic state. In the case of cystic fibrosis (CF), there is a clear hypersusceptibility to respiratory infection with Pseudomonas aeruginosa, as over 80% of individuals with CF suffer from considerable morbidity due to chronic lung infection with this pathogen. Chronic P. aeruginosa infection is also the cause of death in over three-quarters of CF patients [1]. The role that CFTR plays in innate immunity to P. aeruginosa, and how it is compromised in CF patients with mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), are areas of intense interest. The major focus of the study of CFTR has been on its role as an ion channel that conducts chloride into and out of cells [2], regulates bicarbonate and sodium transporter channels, and also interacts with other protein channels with a variety of functions (Table 1). Mutations in CFTR associated with severe lung disease are generally found along with little to no CFTR protein expression in the membranes of airway epithelial cells. In addition, some severe CF is associated with expression of CFTR variant proteins with altered function [3]. However, the specific molecular and cellular aberrations that occur because of the reduction, elimination or dysfunction of mutant CFTR proteins, which account for the hypersusceptibility of CF patients to P. aeruginosa infection, have not been fully elucidated. This review discusses the major hypotheses put forward to understand the function of CFTR in innate immunity to P. aeruginosa.

Although CF is considered a disease wherein there is increased susceptibility to a variety of pathogens, it must be appreciated that, at the beginning of the 21st century, the major clinical problem is with P. aeruginosa. Staphylococcus aureus is often isolated from respiratory secretions of CF patients and, on occasion, from the lung, where it can cause serious disease. But there are no definitive data to show that colonization of the upper respiratory tract by S. aureus is harmful to the patient 4., 5•., although it can cause serious lower-respiratory-tract infections, such as pneumonia and empyema (a grossly purulent effusion). Recent studies suggest that a reduction of S. aureus in sputa of CF patients who are given continuous antistaphylococcal antibiotic therapy leads to increased rates of P. aeruginosa infection [5•]. Whether this is because of a probiotic, protective effect of S. aureus colonization leading to reduced P. aeruginosa colonization or to increased P. aeruginosa infection following use of antistaphylococcal antibiotics, which can change oropharyngeal flora and increase colonization by Gram-negative organisms, is not resolved. Another problem is whether the antibiotics had sufficient penetration into the lung for an effective antistaphylococcal state to be established. Other pathogens, such as Haemophilus influenzae, are also isolated from the sputa of CF patients but there is no understanding of the importance of this finding. A variety of other pathogens, such as Stenotrophomonas maltophilia and Alcaligenes xylosoxidans, are isolated from <10% of patients. Burkholderia cepacia can cause rapid declines in some patients following infection, but only 6% of CF patients are infected with this organism [1]. Overall, the clear predominant pathogen of CF is P. aeruginosa and this must somehow relate to mutant CFTR genes.

Section snippets

CFTR dysfunction and susceptibility to P.aeruginosa infection

One major idea describing how CFTR dysfunction leads to P. aeruginosa and potentially other infections focuses on a disruption in the composition of airway secretions in the CF lung. This may lead to deficient activities of antimicrobial peptides in the airway surface liquid (ASL) that lies just above the apical membrane of airway epithelia, and to defects in mucociliary transport 6., 7., 8., 9.. Deficient antimicrobial peptide activity initially focused on salt-sensitive, cationic,

CFTR as a receptor for P. aeruginosa

Pier and colleagues 26., 27. have proposed a molecular basis for the hypersusceptibility of CF patients to lung infection with P. aeruginosa. The hypothesis is based on the finding that CFTR is an epithelial cell receptor for P. aeruginosa, with CFTR peptide 108–117 binding to the conserved outer-core oligosaccharide of the bacterium. In this sense, CFTR serves as a type of pattern recognition molecule, although with a more limited recognition of bacterial ligands than have other pattern

Other responses of the lung to P. aeruginosa infection

In addition to the CFTR-dependent uptake and cellular shedding of internalized P. aeruginosa, it is now becoming apparent that other key processes in innate immunity to this pathogen are dependent on bacterial–CFTR interactions. Esen et al. [37••] showed that CFTR-dependent epithelial cell ingestion of P. aeruginosa was associated with the activation of the Src-like tyrosine kinases p59Fyn and p60Src and the consequent tyrosine phosphorylation of several eukaryotic proteins. Inhibition of

Conclusions

The overwhelming propensity of CF patients to become infected with P. aeruginosa must be due to a defect in innate immunity associated with lack of expression of wild-type CFTR. It is clear that not one single factor is involved, and the effect of CFTR on the coordinated innate immune response to P. aeruginosa is multifactorial. Almost all of the proposed effects have been controversial, with data both supporting and refuting a role for hypertonicity of ASL and ineffective antimicrobial

Acknowledgements

Research conducted by the author and referred to in this review was conducted under National Institutes of Health Grant HL-58398.

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

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