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Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective

Nature Reviews Microbiology volume 10, pages 841–851 (2012)Cite this article

Subjects

Key Points

  • Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator gene, which encodes a cyclic AMP-regulated chloride ion channel. The mutation results in defective ion transport across epithelial cell surfaces in the upper airways, interfering with the clearance of particles and microbial cells that are trapped in the overlying mucus and resulting in a greatly increased susceptibility to bacterial infection. As a consequence, the airways of patients with CF are nearly always infected with many different bacterial species, but Pseudomonas aeruginosa infection causes the greatest burden of morbidity and mortality.

  • P. aeruginosa infection of the airways of patients with CF begins with a period of recurrent, intermittent colonization from the environment or from a protected niche within the patient, such as the paranasal sinuses. These intermittent infections can be effectively controlled with aggressive antibiotic therapy, but eventually a chronic infection develops that can persist for the rest of the patient's lifetime.

  • Chronic infections of the CF airway by P. aeruginosa thus provide a valuable opportunity to study bacterial evolution in a complex natural environment. These infections are most often clonal, and regular sampling is possible from samples collected when the patients attend clinics. With the recent developments in DNA sequencing and other genome-wide analysis tools, it is now possible to produce a detailed characterization and time-resolved map of the evolutionary trajectories of the infecting bacteria.

  • In the CF lung, P. aeruginosa encounters stressful conditions, including oxidative, nitrosative and cell envelope stress, and antibiotics. The switches in P. aeruginosa gene expression that occur in response to these stresses and to antibiotics have been well characterized, and the global regulators responsible have been identified.

  • Recent tracking of genomic evolution in sequential P. aeruginosa isolates from individual patients has identified a set of genes that were repeatedly found to have acquired non-synonymous mutations. These genes include three global regulators that were known from in vitro work to be important in P. aeruginosa adaptation to the CF lung: mucA, which encodes an inner-membrane-associated anti-σ-factor and controls alginate synthesis; lasR, which encodes a transcriptional regulator of quorum sensing; and rpoN, which encodes an alternative RNA polymerase σ-factor involved in the regulation of virulence gene expression.

Abstract

The airways of patients with cystic fibrosis (CF) are nearly always infected with many different microorganisms. This environment offers warm, humid and nutrient-rich conditions, but is also stressful owing to frequent antibiotic therapy and the host immune response. Pseudomonas aeruginosa is commonly isolated from the airways of patients with CF, where it most often establishes chronic infections that usually persist for the rest of the lives of the patients. This bacterium is a major cause of mortality and morbidity and has therefore been studied intensely. Here, we discuss how P. aeruginosa evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments. We believe that such studies are valuable not only for our understanding of bacterial evolution but also for the future development of new therapeutic strategies to treat severe chronic infections.

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Figure 1: Defects in mucociliary clearance of the CF airway creates opportunities for microbial colonization.
Figure 2: Progression of P. aeruginosa infections in patients with CF.
Figure 3: Regulation network of MucA–σ22.
Figure 4: A model for the typical course of P. aeruginosa colonization and infection in the CF airway.
Figure 5: Rates of mutation accumulation and phenotypic changes in CF-associated isolates of P. aeruginosa.

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Acknowledgements

The authors thank the Danish Agency for Science and Technology and the Lundbeck Foundation for generous support to the cystic fibrosis collaborative project during the past decade.

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Author notes

  1. Lei Yang & Niels Høiby

    Present address: Present address: Department of Biological Engineering, Massachusetts Institute of Technology, Synthetic Biology Center, 500 Technology Square, NE47-277, Cambridge, Massachusetts 02139, USA.,

  2. Anders Folkesson and Lars Jelsbak: These authors contributed equally to this article.

Authors and Affiliations

  1. Department of Systems Biology, Technical University of Denmark, Lyngby, 2800, Denmark

    Anders Folkesson, Lars Jelsbak, Lei Yang & Søren Molin

  2. Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, 2100, Denmark

    Helle Krogh Johansen & Niels Høiby

  3. Institute for International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, 2200, Denmark

    Oana Ciofu

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Glossary

Periciliary fluid

The layer of fluid that is in contact with the surface epithelial cells in the airway.

Polymorphonuclear leukocytes

A class of white blood cells that includes neutrophils, eosinophils and basophils, and is characterized by the possession of multilobed nuclei.

Envelope stress response

A signal transduction pathway that senses and responds to extracytoplasmic stress.

Complement

Part of the innate immune response. The complement system comprises more than 25 proteins that recognize foreign objects and target them for destruction or phagocytosis.

Anti-σ-factor

A negative transcriptional regulator that binds to a target RNA polymerase σ-factor to prevent its activity.

Hypermutability

A mutation rate that is high compared with the average mutation rate for the species.

Chronic rhinosinusitis

In adults: inflammation of the nose and the paranasal sinuses, characterized by two or more symptoms, one of which should be nasal blockage, obstruction, congestion or discharge (anterior or posterior nasal drip). The other symptoms are one or more of the following: facial pain or pressure; a reduction or loss of smell; a cough; endoscopic signs of nasal polyps; mucopurulent discharge (primarily from the middle meatus); oedema or mucosal obstruction (primarily in the middle meatus); and CT changes.

Clonal complex

A group of bacterial isolates, as derived from multilocus sequence typing (MLST) analysis. A clonal complex usually includes isolates that differ from each other at only one of the seven loci analysed by MLST.

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Folkesson, A., Jelsbak, L., Yang, L. et al. Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective. Nat Rev Microbiol 10, 841–851 (2012). https://doi.org/10.1038/nrmicro2907

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