Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Bye, M. R., Ewig, J. M. & Quittell, L. M. Cystic fibrosis. Lung 172, 251–270 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Boucher, R. C. Relationship of airway epithelial ion transport to chronic bronchitis. Proc. Am. Thorac. Soc. 1, 66–70 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Armstrong, D. S. et al. Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis. BMJ 310, 1571–1572 (1995).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  4. 4

    Armstrong, D. S. et al. Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr. Pulmonol. 40, 500–510 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Hoiby, N., Frederiksen, B. & Pressler, T. Eradication of early Pseudomonas aeruginosa infection. J. Cyst. Fibros. 4, 49–54 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Cystic Fibrosis Foundation. Cystic Fibrosis Foundation patient registry 2010 annual data report (Cystic Fibrosis Foundation, 2011).

  7. 7

    Bjarnsholt, T. et al. Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients. Pediatr. Pulmonol. 44, 547–558 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ulrich, M. et al. Alveolar inflammation in cystic fibrosis. J. Cyst. Fibros. 9, 217–227 (2010).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  9. 9

    Yang, L., Jelsbak, L. & Molin, S. Microbial ecology and adaptation in cystic fibrosis airways. Environ. Microbiol. 13, 1682–1689 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hansen, C. R., Pressler, T. & Hoiby, N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J. Cyst. Fibros. 7, 523–530 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Rasmussen, J. et al. CT of the paranasal sinuses is not a valid indicator for sinus surgery in CF patients. J. Cyst. Fibros. 11, 93–99 (2012).

    Article  Google Scholar 

  12. 12

    Harrison, F. Microbial ecology of the cystic fibrosis lung. Microbiology 153, 917–923 (2007).

    CAS  Article  Google Scholar 

  13. 13

    Koch, C. Early infection and progression of cystic fibrosis lung disease. Pediatr. Pulmonol. 34, 232–236 (2002).

    Article  Google Scholar 

  14. 14

    Hoiby, N. & Johansen, H. K. Isolation measures for prevention of infection with respiratory pathogens in cystic fibrosis: a systematic review? J. Hosp. Infect. 65, 374–375 (2007).

    CAS  Article  Google Scholar 

  15. 15

    FitzSimmons, S. C. The changing epidemiology of cystic fibrosis. J. Pediatr. 122, 1–9 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Burns, J. L. et al. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J. Infect. Dis. 183, 444–452 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Johansen, H. K. & Hoiby, N. Seasonal onset of initial colonisation and chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis in Denmark. Thorax 47, 109–111 (1992).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  18. 18

    Doring, G., Taccetti, G., Campana, S., Festini, F. & Mascherini, M. Eradication of Pseudomonas aeruginosa in cystic fibrosis patients. Eur. Respir. J. 27, 653 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Gibson, R. L. et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 167, 841–849 (2003).

    Article  Google Scholar 

  20. 20

    Munck, A. et al. Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization. Pediatr. Pulmonol. 32, 288–292 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Jelsbak, L. et al. Molecular epidemiology and dynamics of Pseudomonas aeruginosa populations in lungs of cystic fibrosis patients. Infect. Immun. 75, 2214–2224 (2007).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  22. 22

    Doring, G. et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur. Respir. J. 16, 749–767 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Doring, G. & Hoiby, N. Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J. Cyst. Fibros. 3, 67–91 (2004).

    Article  Google Scholar 

  24. 24

    Lee, T. W., Brownlee, K. G., Conway, S. P., Denton, M. & Littlewood, J. M. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J. Cyst. Fibros. 2, 29–34 (2003).

    Article  Google Scholar 

  25. 25

    Nichols, D., Chmiel, J. & Berger, M. Chronic inflammation in the cystic fibrosis lung: alterations in inter- and intracellular signaling. Clin. Rev. Allergy Immunol. 34, 146–162 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Regamey, N., Jeffery, P. K., Alton, E. W., Bush, A. & Davies, J. C. Airway remodelling and its relationship to inflammation in cystic fibrosis. Thorax 66, 624–629 (2011).

    Article  Google Scholar 

  27. 27

    Anderson, G. G., Moreau-Marquis, S., Stanton, B. A. & O'Toole, G. A. In vitro analysis of tobramycin-treated Pseudomonas aeruginosa biofilms on cystic fibrosis-derived airway epithelial cells. Infect. Immun. 76, 1423–1433 (2008).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  28. 28

    Aspedon, A., Palmer, K. & Whiteley, M. Microarray analysis of the osmotic stress response in Pseudomonas aeruginosa. J. Bacteriol. 188, 2721–2725 (2006).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  29. 29

    Bagge, N. et al. Pseudomonas aeruginosa biofilms exposed to imipenem exhibit changes in global gene expression and β-lactamase and alginate production. Antimicrob. Agents Chemother. 48, 1175–1187 (2004).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  30. 30

    Cirz, R. T., O'Neill, B. M., Hammond, J. A., Head, S. R. & Romesberg, F. E. Defining the Pseudomonas aeruginosa SOS response and its role in the global response to the antibiotic ciprofloxacin. J. Bacteriol. 188, 7101–7110 (2006).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  31. 31

    Jones, A. K. et al. Activation of the Pseudomonas aeruginosa AlgU regulon through mucA mutation inhibits cyclic AMP/Vfr signaling. J. Bacteriol. 192, 5709–5717 (2010).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  32. 32

    Wu, W., Badrane, H., Arora, S., Baker, H. V. & Jin, S. MucA-mediated coordination of type III secretion and alginate synthesis in Pseudomonas aeruginosa. J. Bacteriol. 186, 7575–7585 (2004).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  33. 33

    Huse, H. K. et al. Parallel evolution in Pseudomonas aeruginosa over 39,000 generations in vivo. mBio 1, e00199–10 (2010).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  34. 34

    Rau, M. H. et al. Early adaptive developments of Pseudomonas aeruginosa after the transition from life in the environment to persistent colonization in the airways of human cystic fibrosis hosts. Environ. Microbiol. 12, 1643–1658 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Yang, L. et al. Evolutionary dynamics of bacteria in a human host environment. Proc. Natl Acad. Sci. USA 108, 7481–7486 (2011). This report outlines the evolutionary dynamics of a transmissible P. aeruginosa clone (DK2) during 35 years of growth in a CF airway.

    CAS  Article  Google Scholar 

  36. 36

    Hull, J., Vervaart, P., Grimwood, K. & Phelan, P. Pulmonary oxidative stress response in young children with cystic fibrosis. Thorax 52, 557–560 (1997).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  37. 37

    Hudson, A. L., Sotirchos, I. M., Davey, M. W. & Hudson, V. M. The activity and hydrogen peroxide sensitivity of the peroxiredoxins from the parasitic nematode Haemonchus contortus. Mol. Biochem. Parasitol. 176, 17–24 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Hudson, V. M. Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. Free Radic. Biol. Med. 30, 1440–1461 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Back, E. I. et al. Antioxidant deficiency in cystic fibrosis: when is the right time to take action? Am. J. Clin. Nutr. 80, 374–384 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Worlitzsch, D. et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J. Clin. Invest. 109, 317–325 (2002).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  41. 41

    Kolpen, M. et al. Polymorphonuclear leucocytes consume oxygen in sputum from chronic Pseudomonas aeruginosa pneumonia in cystic fibrosis. Thorax 65, 57–62 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Hauser, A. R., Jain, M., Bar-Meir, M. & McColley, S. A. Clinical significance of microbial infection and adaptation in cystic fibrosis. Clin. Microbiol. Rev. 24, 29–70 (2011).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  43. 43

    Johansen, H. K. et al. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success? A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection. Pediatr. Pulmonol. 37, 427–432 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lister, P. D., Wolter, D. J. & Hanson, N. D. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin. Microbiol. Rev. 22, 582–610 (2009).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  45. 45

    Bert, F., Branger, C. & Lambert-Zechovsky, N. Identification of PSE and OXA β-lactamase genes in Pseudomonas aeruginosa using PCR-restriction fragment length polymorphism. J. Antimicrob. Chemother. 50, 11–18 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    MacLeod, D. L. et al. Aminoglycoside-resistance mechanisms for cystic fibrosis Pseudomonas aeruginosa isolates are unchanged by long-term, intermittent, inhaled tobramycin treatment. J. Infect. Dis. 181, 1180–1184 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Poole, K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 49, 479–487 (2005).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  48. 48

    Smith, E. E. et al. Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc. Natl Acad. Sci. USA 103, 8487–8492 (2006). This paper describes the genomic analysis of longitudinal isolates of P. aeruginosa sampled from a young patient with CF, and provides a first insight into how this pathogen adapts to its human host.

    CAS  Article  Google Scholar 

  49. 49

    Costerton, J. W., Irvin, R. T. & Cheng, K. J. The bacterial glycocalyx in nature and disease. Annu. Rev. Microbiol. 35, 299–324 (1981).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Cabral, D. A., Loh, B. A. & Speert, D. P. Mucoid Pseudomonas aeruginosa resists nonopsonic phagocytosis by human neutrophils and macrophages. Pediatr. Res. 22, 429–431 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Meshulam, T., Obedeanu, N., Merzbach, D. & Sobel, J. D. Phagocytosis of mucoid and nonmucoid strains of Pseudomonas aeruginosa. Clin. Immunol. Immunopathol. 32, 151–165 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Meshulam, T., Verbrugh, H. A. & Verhoef, J. Opsonization and phagocytosis of mucoid and non-mucoid Pseudomonas aeruginosa strains. Eur. J. Clin. Microbiol. 1, 112–117 (1982).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Simpson, J. A., Smith, S. E. & Dean, R. T. Scavenging by alginate of free radicals released by macrophages. Free Radic. Biol. Med. 6, 347–353 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Pedersen, S. S., Kharazmi, A., Espersen, F. & Hoiby, N. Pseudomonas aeruginosa alginate in cystic fibrosis sputum and the inflammatory response. Infect. Immun. 58, 3363–3368 (1990).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. 55

    Govan, J. R. & Deretic, V. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Microbiol. Rev. 60, 539–574 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  56. 56

    Pedersen, S. S. Lung infection with alginate-producing, mucoid Pseudomonas aeruginosa in cystic fibrosis. APMIS Suppl. 28, 1–79 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Martin, D. W. et al. Mechanism of conversion to mucoidy in Pseudomonas aeruginosa infecting cystic fibrosis patients. Proc. Natl Acad. Sci. USA 90, 8377–8381 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Boucher, J. C., Yu, H., Mudd, M. H. & Deretic, V. Mucoid Pseudomonas aeruginosa in cystic fibrosis: characterization of muc mutations in clinical isolates and analysis of clearance in a mouse model of respiratory infection. Infect. Immun. 65, 3838–3846 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  59. 59

    Wood, L. F. & Ohman, D. E. Identification of genes in the σ22 regulon of Pseudomonas aeruginosa required for cell envelope homeostasis in either the planktonic or the sessile mode of growth. mBio 3, e00094–12 (2012).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  60. 60

    Ramsey, D. M. & Wozniak, D. J. Understanding the control of Pseudomonas aeruginosa alginate synthesis and the prospects for management of chronic infections in cystic fibrosis. Mol. Microbiol. 56, 309–322 (2005).

    CAS  Article  Google Scholar 

  61. 61

    Deretic, V., Schurr, M. J., Boucher, J. C. & Martin, D. W. Conversion of Pseudomonas aeruginosa to mucoidy in cystic fibrosis: environmental stress and regulation of bacterial virulence by alternative sigma factors. J. Bacteriol. 176, 2773–2780 (1994).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  62. 62

    Chitnis, C. E. & Ohman, D. E. Genetic analysis of the alginate biosynthetic gene cluster of Pseudomonas aeruginosa shows evidence of an operonic structure. Mol. Microbiol. 8, 583–593 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    DeVries, C. A. & Ohman, D. E. Mucoid-to-nonmucoid conversion in alginate-producing Pseudomonas aeruginosa often results from spontaneous mutations in algT, encoding a putative alternate sigma factor, and shows evidence for autoregulation. J. Bacteriol. 176, 6677–6687 (1994).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  64. 64

    Wood, L. F. & Ohman, D. E. Use of cell wall stress to characterize σ22 (AlgT/U) activation by regulated proteolysis and its regulon in Pseudomonas aeruginosa. Mol. Microbiol. 72, 183–201 (2009).

    CAS  Article  Google Scholar 

  65. 65

    Wood, L. F., Leech, A. J. & Ohman, D. E. Cell wall-inhibitory antibiotics activate the alginate biosynthesis operon in Pseudomonas aeruginosa: roles of σ22 (AlgT) and the AlgW and Prc proteases. Mol. Microbiol. 62, 412–426 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Ciofu, O., Fussing, V., Bagge, N., Koch, C. & Hoiby, N. Characterization of paired mucoid/non-mucoid Pseudomonas aeruginosa isolates from Danish cystic fibrosis patients: antibiotic resistance, β-lactamase activity and RiboPrinting. J. Antimicrob. Chemother. 48, 391–396 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Gilligan, P. H. Microbiology of airway disease in patients with cystic fibrosis. Clin. Microbiol. Rev. 4, 35–51 (1991).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  68. 68

    Rainey, P. B. & Travisano, M. Adaptive radiation in a heterogeneous environment. Nature. 394, 69–72 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Mowat, E. et al. Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis chronic infections. Am. J. Respir. Crit. Care Med. 183, 1674–1679 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Hansen, S. K. et al. Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection. ISME J. 6, 31–45 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Oliver, A., Canton, R., Campo, P., Baquero, F. & Blazquez, J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 288, 1251–1254 (2000).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  72. 72

    Hassett, D. J. et al. Pseudomonas aeruginosa biofilm infections in cystic fibrosis: insights into pathogenic processes and treatment strategies. Expert Opin. Ther. Targets 14, 117–130 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Fokkens, W. J. et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50, 1–12 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Johansen, H. K. et al. Colonisation and infection of the paranasal sinuses in cystic fibrosis patients is accompanied by a reduced PMN response. J. Cyst. Fibros. 15 May 2012 (doi:10.1016/j.jcf.2012.04.011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Aanaes, K. et al. Decreased mucosal oxygen tension in the maxillary sinuses in patients with cystic fibrosis. J. Cyst. Fibros. 10, 114–120 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Robertson, J. M., Friedman, E. M. & Rubin, B. K. Nasal and sinus disease in cystic fibrosis. Paediatr. Respir. Rev. 9, 213–219 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Mainz, J. G. et al. Concordant genotype of upper and lower airways P.aeruginosa and S.aureus isolates in cystic fibrosis. Thorax 64, 535–540 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Bonestroo, H. J., de Winter-de Groot, K. M., van der Ent, C. K. & Arets, H. G. Upper and lower airway cultures in children with cystic fibrosis: do not neglect the upper airways. J. Cyst. Fibros. 9, 130–134 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    West, S. A., Griffin, A. S., Gardner, A. & Diggle, S. P. Social evolution theory for microorganisms. Nature Rev. Microbiol. 4, 597–607 (2006).

    CAS  Article  Google Scholar 

  80. 80

    Hoffman, L. R. et al. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J. Cyst. Fibros. 8, 66–70 (2009).

    CAS  Article  Google Scholar 

  81. 81

    D'Argenio, D. A. et al. Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients. Mol. Microbiol. 64, 512–533 (2007).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  82. 82

    Cramer, N. et al. Microevolution of the major common Pseudomonas aeruginosa clones C and PA14 in cystic fibrosis lungs. Environ. Microbiol. 13, 1690–1704 (2011).

    CAS  Article  Google Scholar 

  83. 83

    Blount, Z. D., Borland, C. Z. & Lenski, R. E. Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli. Proc. Natl Acad. Sci. USA 105, 7899–7906 (2008).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  84. 84

    Weinreich, D. M., Delaney, N. F., Depristo, M. A. & Hartl, D. L. Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312, 111–114 (2006).

    CAS  Google Scholar 

  85. 85

    Woods, R. J. et al. Second-order selection for evolvability in a large Escherichia coli population. Science 331, 1433–1436 (2011).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  86. 86

    Mahenthiralingam, E., Campbell, M. E., Foster, J., Lam, J. S. & Speert, D. P. Random amplified polymorphic DNA typing of Pseudomonas aeruginosa isolates recovered from patients with cystic fibrosis. J. Clin. Microbiol. 34, 1129–1135 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  87. 87

    Romling, U. et al. Epidemiology of chronic Pseudomonas aeruginosa infections in cystic fibrosis. J. Infect. Dis. 170, 1616–1621 (1994).

    CAS  Article  Google Scholar 

  88. 88

    Jelsbak, L. et al. Molecular epidemiology and dynamics of Pseudomonas aeruginosa populations in lungs of cystic fibrosis patients. Infect. Immun. 75, 2214–2224 (2007).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  89. 89

    Yang, L. et al. In situ growth rates and biofilm development of Pseudomonas aeruginosa populations in chronic lung infections. J. Bacteriol. 190, 2767–2776 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Lieberman, T. D. et al. Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes. Nature Genet. 43, 1275–1280 (2011). This article provides an example of genomic evolution in a CF-associated pathogen.

    CAS  Article  Google Scholar 

  91. 91

    Cramer, N., Wiehlmann, L. & Tummler, B. Clonal epidemiology of Pseudomonas aeruginosa in cystic fibrosis. Int. J. Med. Microbiol. 300, 526–533 (2010).

    Article  Google Scholar 

  92. 92

    Bragonzi, A. et al. Pseudomonas aeruginosa microevolution during cystic fibrosis lung infection establishes clones with adapted virulence. Am. J. Respir. Crit. Care Med. 180, 138–145 (2009).

    Article  Google Scholar 

  93. 93

    Hoboth, C. et al. Dynamics of adaptive microevolution of hypermutable Pseudomonas aeruginosa during chronic pulmonary infection in patients with cystic fibrosis. J. Infect. Dis. 200, 118–130 (2009).

    CAS  Article  Google Scholar 

  94. 94

    Hogardt, M. & Heesemann, J. Adaptation of Pseudomonas aeruginosa during persistence in the cystic fibrosis lung. Int. J. Med. Microbiol. 300, 557–562 (2010).

    CAS  Article  Google Scholar 

  95. 95

    Barrick, J. E. et al. Genome evolution and adaptation in a long-term experiment with Escherichia coli. Nature 461, 1243–1247 (2009). This work uses laboratory evolution experiments combined with genomic analysis to investigate evolution in action.

    CAS  Article  Google Scholar 

  96. 96

    Cooper, V. S. & Lenski, R. E. The population genetics of ecological specialization in evolving Escherichia coli populations. Nature 407, 736–739 (2000).

    CAS  Article  Google Scholar 

  97. 97

    Silander, O. K., Tenaillon, O. & Chao, L. Understanding the evolutionary fate of finite populations: the dynamics of mutational effects. PLoS Biol. 5, e94 (2007).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  98. 98

    Holder, K. K. & Bull, J. J. Profiles of adaptation in two similar viruses. Genetics 159, 1393–1404 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  99. 99

    Hansen, S. K. et al. Characterization of a Pseudomonas putida rough variant evolved in a mixed-species biofilm with Acinetobacter sp. strain C6. J. Bacteriol. 189, 4932–4943 (2007).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  100. 100

    Boles, B. R., Thoendel, M. & Singh, P. K. Self-generated diversity produces “insurance effects” in biofilm communities. Proc. Natl Acad. Sci. USA 101, 16630–16635 (2004).

    CAS  Article  Google Scholar 

  101. 101

    Keymer, J. E., Galajda, P., Muldoon, C., Park, S. & Austin, R. H. Bacterial metapopulations in nanofabricated landscapes. Proc. Natl Acad. Sci. USA 103, 17290–17295 (2006).

    CAS  Article  Google Scholar 

  102. 102

    Wilder, C. N., Allada, G. & Schuster, M. Instantaneous within-patient diversity of Pseudomonas aeruginosa quorum-sensing populations from cystic fibrosis lung infections. Infect. Immun. 77, 5631–5639 (2009).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  103. 103

    Hunter, P. The great leap forward. Major evolutionary jumps might be caused by changes in gene regulation rather than the emergence of new genes. EMBO Rep. 9, 608–611 (2008).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  104. 104

    Wang, L. et al. Divergence involving global regulatory gene mutations in an Escherichia coli population evolving under phosphate limitation. Genome Biol. Evol. 2, 478–487 (2010).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  105. 105

    Zambrano, M. M., Siegele, D. A., Almiron, M., Tormo, A. & Kolter, R. Microbial competition: Escherichia coli mutants that take over stationary phase cultures. Science 259, 1757–1760 (1993).

    CAS  Article  Google Scholar 

  106. 106

    Conrad, T. M., Lewis, N. E. & Palsson, B. O. Microbial laboratory evolution in the era of genome-scale science. Mol. Syst. Biol. 7, 509 (2011).

    PubMed Central  Article  PubMed  Google Scholar 

  107. 107

    Sumby, P., Whitney, A. R., Graviss, E. A., DeLeo, F. R. & Musser, J. M. Genome-wide analysis of group a streptococci reveals a mutation that modulates global phenotype and disease specificity. PLoS Pathog. 2, e5 (2006).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  108. 108

    Giraud, A. et al. Dissecting the genetic components of adaptation of Escherichia coli to the mouse gut. PLoS Genet. 4, e2 (2008).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  109. 109

    Kresse, A. U., Dinesh, S. D., Larbig, K. & Romling, U. Impact of large chromosomal inversions on the adaptation and evolution of Pseudomonas aeruginosa chronically colonizing cystic fibrosis lungs. Mol. Microbiol. 47, 145–158 (2003).

    CAS  Article  Google Scholar 

  110. 110

    Klockgether, J., Cramer, N., Wiehlmann, L., Davenport, C. F. & Tummler, B. Pseudomonas aeruginosa genomic structure and diversity. Front. Microbiol. 2, 150 (2011).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  111. 111

    Hindre, T., Knibbe, C., Beslon, G. & Schneider, D. New insights into bacterial adaptation through in vivo and in silico experimental evolution. Nature Rev. Microbiol. 10, 352–365 (2012). This review describes how experimental evolution studies have provided fundamental insight into bacterial adaptive mechanisms.

    CAS  Article  Google Scholar 

  112. 112

    Willner, D. et al. Spatial distribution of microbial communities in the cystic fibrosis lung. ISME J. 6, 471–474 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Zhao, J. et al. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc. Natl Acad. Sci. USA 109, 5809–5814 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Klepac-Ceraj, V. et al. Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa. Environ. Microbiol. 12, 1293–1303 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Kleinstreuer, C., Zhang, Z. and Donohue, J. F. Targeted drug-aerosol delivery in the human respiratory system. Annu. Rev. Biomed. Eng. 10, 195–220 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Winnie, G. B. & Cowan, R. G. Respiratory tract colonization with Pseudomonas aeruginosa in cystic fibrosis: correlations between anti-Pseudomonas aeruginosa antibody levels and pulmonary function. Pediatr. Pulmonol. 10, 92–100 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Martin, D. W., Schurr, M. J., Yu, H. & Deretic, V. Analysis of promoters controlled by the putative sigma factor AlgU regulating conversion to mucoidy in Pseudomonas aeruginosa: relationship to σE and stress response. J. Bacteriol. 176, 6688–6696 (1994).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Søren Molin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing