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Pseudomonas aeruginosa adaptation and evolution in patients with cystic fibrosis

Nature Reviews Microbiology volume 19, pages 331–342 (2021)Cite this article

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Abstract

Intense genome sequencing of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) airways has shown inefficient eradication of the infecting bacteria, as well as previously undocumented patient-to-patient transmission of adapted clones. However, genome sequencing has limited potential as a predictor of chronic infection and of the adaptive state during infection, and thus there is increasing interest in linking phenotypic traits to the genome sequences. Phenotypic information ranges from genome-wide transcriptomic analysis of patient samples to determination of more specific traits associated with metabolic changes, stress responses, antibiotic resistance and tolerance, biofilm formation and slow growth. Environmental conditions in the CF lung shape both genetic and phenotypic changes of P. aeruginosa during infection. In this Review, we discuss the adaptive and evolutionary trajectories that lead to early diversification and late convergence, which enable P. aeruginosa to succeed in this niche, and we point out how knowledge of these biological features may be used to guide diagnosis and therapy.

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Fig. 1: Adaptation of Pseudomonas aeruginosa in cystic fibrosis airways.
Fig. 2: Metabolic and physiologic adaptation of Pseudomonas aeruginosa to the cystic fibrosis environment.
Fig. 3: Response and adaptation of Pseudomonas aeruginosa to antibiotics and the host immune system.

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References

  1. Ratjen, F. & Döring, G. Cystic fibrosis. Lancet 361, 681–689 (2003).

    PubMed  CAS  Google Scholar 

  2. Marvig, R. L., Sommer, L. M., Molin, S. & Johansen, H. K. Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis. Nat. Genet. 47, 57–64 (2015). This paper presents the comprehensive genomic analysis of a collection of longitudinal P. aeruginosa isolates from several patients with early-stage infections, used to define a set of pathoadaptive genes.

    PubMed  CAS  Google Scholar 

  3. Marvig, R. L., Johansen, H. K., Molin, S. & Jelsbak, L. Genome analysis of a transmissible lineage of Pseudomonas aeruginosa reveals pathoadaptive mutations and distinct evolutionary paths of hypermutators. PLoS Genet. 9, e1003741 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Williams, D. et al. Divergent, coexisting Pseudomonas aeruginosa lineages in chronic cystic fibrosis lung infections. Am. J. Respir. Crit. Care Med. 191, 775–785 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. 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).

    PubMed  CAS  Google Scholar 

  6. Marvig, R. L. et al. Within-host evolution of Pseudomonas aeruginosa reveals adaptation toward iron acquisition from hemoglobin. mBio 5, e00966–e01014 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Klockgether, J., Cramer, N., Fischer, S., Wiehlmann, L. & Tümmler, B. Long-term microevolution of Pseudomonas aeruginosa differs between mildly and severely affected cystic fibrosis lungs. Am. J. Respir. Cell Mol. Biol. 59, 246–256 (2018).

    PubMed  CAS  Google Scholar 

  8. Fischer, S. et al. Multilocus amplicon sequencing of Pseudomonas aeruginosa cystic fibrosis airways isolates collected prior to and after early antipseudomonal chemotherapy. J. Cyst. Fibros. 16, 346–352 (2016).

    PubMed  Google Scholar 

  9. Oliver, A., Cantón, R., Campo, P., Baquero, F. & Blázquez, J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 288, 1251–1253 (2000). This paper is the first to describe the high prevalence of hyper-mutator strains of P. aeruginosa in CF lung samples.

    PubMed  CAS  Google Scholar 

  10. Boulant, T. et al. A 2.5-years within-patient evolution of a Pseudomonas aeruginosa with in vivo acquisition of ceftolozane–tazobactam and ceftazidime–avibactam resistance upon treatment. Antimicrob. Agents Chemother. 63, e01637-19 (2019).

    PubMed Central  CAS  Google Scholar 

  11. Tueffers, L. et al. Pseudomonas aeruginosa populations in the cystic fibrosis lung lose susceptibility to newly applied β-lactams within 3 days. J. Antimicrob. Chemother. 74, 2916–2925 (2019).

    PubMed  CAS  Google Scholar 

  12. Gabrielaite, M., Johansen, H. K., Molin, S., Nielsen, F. C. & Marvig, R. L. Gene loss and acquisition in lineages of bacteria evolving in a human host environment. mBio 11, e02359-20 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Rau, M. H., Marvig, R. L., Ehrlich, G. D., Molin, S. & Jelsbak, L. Deletion and acquisition of genomic content during early stage adaptation of Pseudomonas aeruginosa to a human host environment. Environ. Microbiol. 14, 2200–2211 (2012).

    PubMed  CAS  Google Scholar 

  14. Hocquet, D. et al. Pyomelanin-producing Pseudomonas aeruginosa selected during chronic infections have a large chromosomal deletion which confers resistance to pyocins: intraspecific competition and pathogen evolution. Environ. Microbiol. 18, 3482–3493 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Hwang, W. & Yoon, S. S. Virulence characteristics and an action mode of antibiotic resistance in multidrug-resistant Pseudomonas aeruginosa. Sci. Rep. 9, 487 (2019).

    PubMed  PubMed Central  Google Scholar 

  16. Brown-Jaque, M. et al. Detection of bacteriophage particles containing antibiotic resistance genes in the sputum of cystic fibrosis patients. Front. Microbiol. 9, 856 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Winstanley, C. et al. Newly introduced genomic prophage islands are critical determinants of in vivo competitiveness in the Liverpool Epidemic Strain of Pseudomonas aeruginosa. Genome Res. 19, 12–23 (2008).

    PubMed  Google Scholar 

  18. Chung, J. C. S. et al. Genomic variation among contemporary Pseudomonas aeruginosa isolates from chronically infected cystic fibrosis patients. J. Bacteriol. 194, 4857–4866 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Weiser, R. et al. Not all Pseudomonas aeruginosa are equal: strains from industrial sources possess uniquely large multireplicon genomes. Microb. Genom. 5, e000276 (2019).

    PubMed Central  Google Scholar 

  20. Lee, D. G. et al. Genomic analysis reveals that Pseudomonas aeruginosa virulence is combinatorial. Genome Biol. 7, R90 (2006).

    PubMed  PubMed Central  Google Scholar 

  21. Rossi, E., Falcone, M., Molin, S. & Johansen, H. K. High-resolution in situ transcriptomics of Pseudomonas aeruginosa unveils genotype independent patho-phenotypes in cystic fibrosis lungs. Nat. Commun. 9, 3459 (2018). This metatranscriptomic investigation of P. aeruginosa representing global gene expression in the CF lung shows that the expression profile reflects the lung environment with only minor influence from the bacterial genotype.

    PubMed  PubMed Central  Google Scholar 

  22. Cornforth, D. M. et al. Pseudomonas aeruginosa transcriptome during human infection. Proc. Natl Acad. Sci. USA 115, 201717525 (2018).

    Google Scholar 

  23. Kordes, A. et al. Genetically diverse Pseudomonas aeruginosa populations display similar transcriptomic profiles in a cystic fibrosis explanted lung. Nat. Commun. 10, 3397 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. Wu, X. et al. In vivo proteome of Pseudomonas aeruginosa in airways of cystic fibrosis patients. J. Proteome. Res.18, 2601–2612 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Yang, L. et al. Evolutionary dynamics of bacteria in a human host environment. Proc. Natl Acad. Sci. USA 108, 7481–7486 (2011).

    PubMed  CAS  PubMed Central  Google Scholar 

  26. Stressmann, F. A. et al. Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience. Thorax 67, 867–873 (2012).

    PubMed  Google Scholar 

  27. Smith, D. J. et al. Pyrosequencing reveals transient cystic fibrosis lung microbiome changes with intravenous antibiotics. Eur. Respir. J. 44, 922–930 (2014).

    PubMed  CAS  Google Scholar 

  28. Daniels, T. W. V. et al. Impact of antibiotic treatment for pulmonary exacerbations on bacterial diversity in cystic fibrosis. J. Cyst. Fibros. 12, 22–28 (2013).

    PubMed  CAS  Google Scholar 

  29. Bartell, J. A. et al. Evolutionary highways to persistent bacterial infection. Nat. Commun. 10, 629 (2019). This comprehensive phenotypic analysis of a collection of longitudinal P. aeruginosa isolates from several patients with CF with early-stage infections shows both diversity generation and convergence of specific traits.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Folkesson, A. et al. Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective. Nat. Rev. Microbiol. 10, 841–851 (2012).

    PubMed  CAS  Google Scholar 

  31. Schick, A. & Kassen, R. Rapid diversification of Pseudomonas aeruginosa in cystic fibrosis lung-like conditions. Proc. Natl Acad. Sci. USA 115, 201721270 (2018).

    Google Scholar 

  32. Markussen, T. et al. Environmental heterogeneity drives within-host diversification and evolution of Pseudomonas aeruginosa. mBio 5, e01592–e01614 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Clark, S. T., Guttman, D. S. & Hwang, D. M. Diversification of Pseudomonas aeruginosa within the cystic fibrosis lung and its effects on antibiotic resistance. FEMS Microbiol. Lett. 365, fny026 (2018).

    Google Scholar 

  34. Jorth, P. et al. Regional isolation drives bacterial diversification within cystic fibrosis lungs. Cell Host Microbe 18, 307–319 (2015). This dissection of explanted CF lungs documents adaptive radiation as a main cause of population diversity in the CF lung.

    PubMed  PubMed Central  CAS  Google Scholar 

  35. Alvarez-Ortega, C. & Harwood, C. S. Responses of Pseudomonas aeruginosa to low oxygen indicate that growth in the cystic fibrosis lung is by aerobic respiration. Mol. Microbiol. 65, 153–165 (2007).

    PubMed  PubMed Central  Google Scholar 

  36. Wauven, C. V., Piérard, A., Kley-Raymann, M. & Haas, D. Pseudomonas aeruginosa mutants affected in anaerobic growth on arginine: evidence for a four-gene cluster encoding the arginine deiminase pathway. J. Bacteriol. 160, 928–934 (1984).

    Google Scholar 

  37. Eschbach, M. et al. Long-term anaerobic survival of the opportunistic pathogen Pseudomonas aeruginosa via pyruvate fermentation. J. Bacteriol. 186, 4596–4604 (2004).

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Schreiber, K. et al. Anaerobic survival of Pseudomonas aeruginosa by pyruvate fermentation requires an Usp-type stress protein. J. Bacteriol. 188, 659–668 (2006).

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Alonso, A., Rojo, F. & Martinez, J. L. Environmental and clinical isolates of Pseudomonas aeruginosa show pathogenic and biodegradative properties irrespective of their origin. Environ. Microbiol. 1, 421–430 (1999).

    PubMed  CAS  Google Scholar 

  40. Palmer, K. L., Aye, L. M. & Whiteley, M. Nutritional cues control Pseudomonas aeruginosa multicellular behavior in cystic fibrosis sputum. J. Bacteriol. 189, 8079–8087 (2007).

    PubMed  PubMed Central  CAS  Google Scholar 

  41. La Rosa, R., Johansen, H. K. & Molin, S. Convergent metabolic specialization through distinct evolutionary paths in Pseudomonas aeruginosa. mBio 9, e00269–e00318 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  42. La Rosa, R., Johansen, H. K. & Molin, S. Adapting to the airways: metabolic requirements of Pseudomonas aeruginosa during the infection of cystic fibrosis patients. Metabolites 9, 234 (2019).

    PubMed Central  CAS  Google Scholar 

  43. Crabbé, A., Jensen, P. Ø., Bjarnsholt, T. & Coenye, T. Antimicrobial tolerance and metabolic adaptations in microbial biofilms. Trends Microbiol. 27, 850–863 (2019).

    PubMed  Google Scholar 

  44. Stokes, J. M., Lopatkin, A. J., Lobritz, M. A. & Collins, J. J. Bacterial metabolism and antibiotic efficacy. Cell Metab. 30, 251–259 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Singh, P. K. et al. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407, 762–764 (2000).

    CAS  PubMed  Google Scholar 

  46. Bjarnsholt, T. et al. The in vivo biofilm. Trends Microbiol. 21, 466–474 (2013).

    PubMed  CAS  Google Scholar 

  47. Goodman, A. L. et al. A signaling network reciprocally regulates genes associated with acute infection and chronic persistence in Pseudomonas aeruginosa. Dev. Cell 7, 745–754 (2004).

    PubMed  CAS  Google Scholar 

  48. Waters, V. J. et al. Reconciling antimicrobial susceptibility testing and clinical response in antimicrobial treatment of chronic cystic fibrosis lung infections. Clin. Infect. Dis. 69, 1812–1816 (2019).

    PubMed  CAS  Google Scholar 

  49. Botelho, J., Grosso, F. & Peixe, L. Antibiotic resistance in Pseudomonas aeruginosa — mechanisms, epidemiology and evolution. Drug Resist. Updat. 44, 100640 (2019).

    PubMed  Google Scholar 

  50. Hooper, D. C. & Jacoby, G. A. Mechanisms of drug resistance: quinolone resistance. Ann. N. Y. Acad. Sci. 1354, 12–31 (2017).

    Google Scholar 

  51. Halfon, Y. et al. Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate. Proc. Natl Acad. Sci. USA 116, 22275–22281 (2019).

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Jochumsen, N. et al. The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is shaped by strong epistatic interactions. Nat. Commun. 7, 13002 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  53. Jorth, P. et al. Evolved aztreonam resistance is multifactorial and can produce hypervirulence in Pseudomonas aeruginosa. mBio 8, e00517–e00517 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  54. López-Causapé, C. et al. Evolution of the Pseudomonas aeruginosa mutational resistome in an international cystic fibrosis clone. Sci. Rep. 7, 5555 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. López-Causapé, C., Cabot, G., Barrio-Tofiño, E. D. & Oliver, A. The versatile mutational resistome of Pseudomonas aeruginosa. Front. Microbiol. 9, 685 (2018).

    PubMed  PubMed Central  Google Scholar 

  56. Frimodt-Møller, J. et al. Mutations causing low level antibiotic resistance ensure bacterial survival in antibiotic-treated hosts. Sci. Rep. 8, 12512 (2018).

    PubMed  PubMed Central  Google Scholar 

  57. Ciofu, O. & Tolker-Nielsen, T. Tolerance and resistance of Pseudomonas aeruginosa biofilms to antimicrobial agents—how P. aeruginosa can escape antibiotics. Front. Microbiol. 10, 913 (2019).

    PubMed  PubMed Central  Google Scholar 

  58. Secor, P. R., Michaels, L. A., Ratjen, A., Jennings, L. K. & Singh, P. K. Entropically driven aggregation of bacteria by host polymers promotes antibiotic tolerance in Pseudomonas aeruginosa. Proc. Natl Acad. Sci. USA 115, 10780–10785 (2018).

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Jennings, L. K. et al. Pel is a cationic exopolysaccharide that cross-links extracellular DNA in the Pseudomonas aeruginosa biofilm matrix. Proc. Natl Acad. Sci. USA 112, 11353–11358 (2015).

    PubMed  CAS  PubMed Central  Google Scholar 

  60. Burgener, E. B. et al. Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis. Sci. Transl Med. 11, eaau9748 (2019).

    PubMed  PubMed Central  Google Scholar 

  61. Balaban, N. Q. et al. Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 441–448 (2019). This review of the literature describes the phenomenon of persisters — surviving subpopulations of bacteria treated with antibiotics — and clarifies the biology and experimental conditions for monitoring persister development in bacterial populations.

    PubMed  PubMed Central  CAS  Google Scholar 

  62. Andersson, D. I., Nicoloff, H. & Hjort, K. Mechanisms and clinical relevance of bacterial heteroresistance. Nat. Rev. Microbiol. 17, 479–496 (2019). This review of a novel mechanism, heteroresistance, adds to survival of antibiotic treatment in bacterial populations.

    PubMed  CAS  Google Scholar 

  63. Mulcahy, L. R., Burns, J. L., Lory, S. & Lewis, K. Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. J. Bacteriol. 192, 6191–6199 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  64. Bartell, J. et al. Bacterial persisters in long-term infection: emergence and fitness in a complex host environment. Preprint at bioRxiv https://doi.org/10.1101/561589 (2019).

    Article  Google Scholar 

  65. Nicoloff, H., Hjort, K., Levin, B. R. & Andersson, D. I. The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification. Nat. Microbiol. 4, 504–514 (2019).

    PubMed  CAS  Google Scholar 

  66. Hermes, D. M. et al. Evaluation of heteroresistance to polymyxin B among carbapenem-susceptible and -resistant Pseudomonas aeruginosa. J. Med. Microbiol. 62, 1184–1189 (2013).

    PubMed  Google Scholar 

  67. Mei, S., Gao, Y., Zhu, C., Dong, C. & Chen, Y. Research of the heteroresistance of Pseudomonas aeruginosa to imipenem. Int. J. Clin. Exp. Med. 8, 6129–6132 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. He, J. et al. Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections. Int. J. Antimicrob. Agents 51, 413–421 (2017).

    PubMed  Google Scholar 

  69. Pournaras, S. et al. Characterization of clinical isolates of Pseudomonas aeruginosa heterogeneously resistant to carbapenems. J. Med. Microbiol. 56, 66–70 (2007).

    PubMed  CAS  Google Scholar 

  70. Juhász, E., Iván, M., Pintér, E., Pongrácz, J. & Kristóf, K. Colistin resistance among blood culture isolates at a tertiary care centre in Hungary. J. Glob. Antimicrob. Resist 11, 167–170 (2017).

    PubMed  Google Scholar 

  71. Imlay, J. & Linn, S. DNA damage and oxygen radical toxicity. Science 240, 1302–1309 (1988).

    PubMed  CAS  Google Scholar 

  72. Imlay, J. A. Iron–sulphur clusters and the problem with oxygen. Mol. Microbiol. 59, 1073–1082 (2006).

    PubMed  Google Scholar 

  73. Ernst, R. K. et al. The Pseudomonas aeruginosa lipid A deacylase: selection for expression and loss within the cystic fibrosis airway. J. Bacteriol. 188, 191–201 (2006).

    PubMed  PubMed Central  CAS  Google Scholar 

  74. Ernst, R. K. et al. Unique lipid A modifications in Pseudomonas aeruginosa isolated from the airways of patients with cystic fibrosis. J. Infect. Dis. 196, 1088–1092 (2007).

    PubMed  CAS  Google Scholar 

  75. Hancock, R. E. et al. Pseudomonas aeruginosa isolates from patients with cystic fibrosis: a class of serum-sensitive, nontypable strains deficient in lipopolysaccharide O side chains. Infect. Immun. 42, 170–177 (1983).

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Kim, S. et al. Bacterial ornithine lipid, a surrogate membrane lipid under phosphate-limiting conditions, plays important roles in bacterial persistence and interaction with host. Environ. Microbiol. 20, 3992–4008 (2018).

    PubMed  CAS  Google Scholar 

  77. Jia, J., Wang, Y., Zhou, L. & Jin, S. Expression of Pseudomonas aeruginosa toxin ExoS effectively induces apoptosis in host cells. Infect. Immun. 74, 6557–6570 (2006).

    PubMed  PubMed Central  CAS  Google Scholar 

  78. Broquet, A. & Asehnoune, K. Apoptosis induced by Pseudomonas aeruginosa: a lonely killer? Microb. Biotechnol. 8, 49–51 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. Burstein, D. et al. Novel type III effectors in Pseudomonas aeruginosa. mBio 6, e00161–e00215 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. Malhotra, S., Limoli, D. H., English, A. E., Parsek, M. R. & Wozniak, D. J. Mixed communities of mucoid and nonmucoid Pseudomonas aeruginosa exhibit enhanced resistance to host antimicrobials. mBio 9, e00275–e00318 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  81. Leid, J. G. et al. The exopolysaccharide alginate protects Pseudomonas aeruginosa biofilm bacteria from IFN-γ-mediated macrophage killing. J. Immunol. 175, 7512–7518 (2005).

    PubMed  CAS  Google Scholar 

  82. Pier, G. B., Coleman, F., Grout, M., Franklin, M. & Ohman, D. E. Role of alginate O acetylation in resistance of mucoid Pseudomonas aeruginosa to opsonic phagocytosis. Infect. Immun. 69, 1895–1901 (2001).

    PubMed  PubMed Central  CAS  Google Scholar 

  83. Pestrak, M. J. et al. Pseudomonas aeruginosa rugose small-colony variants evade host clearance, are hyper-inflammatory, and persist in multiple host environments. PLoS Pathog. 14, e1006842 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. Sweere, J. M. et al. Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science 363, eaat9691 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  85. Fothergill, J. L., Mowat, E., Ledson, M. J., Walshaw, M. J. & Winstanley, C. Fluctuations in phenotypes and genotypes within populations of Pseudomonas aeruginosa in the cystic fibrosis lung during pulmonary exacerbations. J. Med. Microbiol. 59, 472–481 (2010).

    PubMed  CAS  Google Scholar 

  86. 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).

    PubMed  Google Scholar 

  87. Jiricny, N. et al. Loss of social behaviours in populations of Pseudomonas aeruginosa infecting lungs of patients with cystic fibrosis. PLoS ONE 9, e83124 (2014).

    PubMed  PubMed Central  Google Scholar 

  88. Andersen, S. B., Marvig, R. L., Molin, S., Johansen, H. K. & Griffin, A. S. Long-term social dynamics drive loss of function in pathogenic bacteria. Proc. Natl Acad. Sci. USA 112, 10756–10761 (2015).

    PubMed  CAS  PubMed Central  Google Scholar 

  89. Winstanley, C., O’Brien, S. & Brockhurst, M. A. Pseudomonas aeruginosa evolutionary adaptation and diversification in cystic fibrosis chronic lung infections. Trends Microbiol. 24, 327–337 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  90. Andersen, S. B. et al. Privatisation rescues function following loss of cooperation. eLife 7, e38594 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. Khaledi, A. et al. Predicting antimicrobial resistance in Pseudomonas aeruginosa with machine learning-enabled molecular diagnostics. EMBO Mol. Med. 12, e10264 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  92. Moradali, M. F., Ghods, S. & Rehm, B. H. A. Pseudomonas aeruginosa lifestyle: a paradigm for adaptation, survival, and persistence. Front. Cell Infect. Microbiol. 7, 39 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Crone, S. et al. The environmental occurrence of Pseudomonas aeruginosa. APMIS 128, 220–231 (2019).

    PubMed  Google Scholar 

  94. Silby, M. W., Winstanley, C., Godfrey, S. A. C., Levy, S. B. & Jackson, R. W. Pseudomonas genomes: diverse and adaptable. FEMS Microbiol. Rev. 35, 652–680 (2011).

    PubMed  CAS  Google Scholar 

  95. Freschi, L. et al. The Pseudomonas aeruginosa pan-genome provides new insights on its population structure, horizontal gene transfer, and pathogenicity. Genome Biol. Evol. 11, 109–120 (2018).

    PubMed Central  Google Scholar 

  96. Turner, K. H., Wessel, A. K., Palmer, G. C., Murray, J. L. & Whiteley, M. Essential genome of Pseudomonas aeruginosa in cystic fibrosis sputum. Proc. Natl Acad. Sci. USA 112, 4110–4115 (2015).

    PubMed  CAS  PubMed Central  Google Scholar 

  97. Klockgether, J., Cramer, N., Wiehlmann, L., Davenport, C. F. & Tümmler, B. Pseudomonas aeruginosa genomic structure and diversity. Front. Microbiol. 2, 150 (2011). This paper presents a thorough characterization and profiling of the P. aeruginosa genome and its insertions and plasmids.

    PubMed  PubMed Central  CAS  Google Scholar 

  98. Stewart, L. et al. Draft genomes of 12 host-adapted and environmental isolates of Pseudomonas aeruginosa and their positions in the core genome phylogeny. Pathog. Dis. 71, 20–25 (2013).

    PubMed  Google Scholar 

  99. Walker, T. S. et al. Pseudomonas aeruginosa–plant root interactions. pathogenicity, biofilm formation, and root exudation. Plant Physiol. 134, 320–331 (2003).

    PubMed  Google Scholar 

  100. Mushin, R. & Ziv, G. An epidemiological study of Pseudomonas aeruginosa in cattle and other animals by pyocine typing. J. Hyg. 71, 113–122 (1973).

    PubMed  CAS  PubMed Central  Google Scholar 

  101. Haenni, M. et al. Population structure and antimicrobial susceptibility of Pseudomonas aeruginosa from animal infections in France. BMC Vet. Res. 11, 9 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. Eklöf, J. et al. Pseudomonas aeruginosa and risk of death and exacerbations in patients with chronic obstructive pulmonary disease: an observational cohort study of 22,053 patients. Clin. Microbiol. Infec. 26, 227–234 (2019).

    Google Scholar 

  103. Barbier, F., Andremont, A., Wolff, M. & Bouadma, L. Hospital-acquired pneumonia and ventilator-associated pneumonia: recent advances in epidemiology and management. Curr. Opin. Pulm. Med. 19, 216–228 (2013).

    PubMed  Google Scholar 

  104. Kerr, K. G. & Snelling, A. M. Pseudomonas aeruginosa: a formidable and ever-present adversary. J. Hosp. Infect. 73, 338–344 (2009).

    PubMed  CAS  Google Scholar 

  105. Horcajada, J. P. et al. Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin. Microbiol. Rev. 32, e00031–e00119 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  106. Pendleton, J. N., Gorman, S. P. & Gilmore, B. F. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti Infect. Ther. 11, 297–308 (2013).

    PubMed  CAS  Google Scholar 

  107. Scotet, V., L’Hostis, C. & Férec, C. The changing epidemiology of cystic fibrosis: incidence, survival and impact of the CFTR gene discovery. Genes 11, 589 (2020).

    PubMed Central  CAS  Google Scholar 

  108. Bell, S. C. et al. The future of cystic fibrosis care: a global perspective. Lancet Respir. Med. 8, 65–124 (2019).

    PubMed  PubMed Central  Google Scholar 

  109. 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. Pulm. 37, 427–432 (2004).

    Google Scholar 

  110. Chaudary, N. Triplet CFTR modulators: future prospects for treatment of cystic fibrosis. Ther. Clin. Risk Manag. 14, 2375–2383 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  111. Frost, F. J., Nazareth, D. S., Charman, S. C., Winstanley, C. & Walshaw, M. J. Ivacaftor is associated with reduced lung infection by key cystic fibrosis pathogens. A cohort study using national registry data. Ann. Am. Thorac. Soc. 16, 1375–1382 (2019).

    PubMed  Google Scholar 

  112. Frimmersdorf, E., Horatzek, S., Pelnikevich, A., Wiehlmann, L. & Schomburg, D. How Pseudomonas aeruginosa adapts to various environments: a metabolomic approach. Environ. Microbiol. 12, 1734–1747 (2010).

    PubMed  CAS  Google Scholar 

  113. Nikel, P. I., Martínez-García, E. & Lorenzo, V. de. Biotechnological domestication of pseudomonads using synthetic biology. Nat. Rev. Microbiol. 12, 368–379 (2014).

    PubMed  CAS  Google Scholar 

  114. Dolan, S. K. et al. Contextual flexibility in Pseudomonas aeruginosa central carbon metabolism during growth in single carbon sources. mBio 11, e02684–e02719 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  115. Perinbam, K., Chacko, J. V., Kannan, A., Digman, M. A. & Siryaporn, A. A shift in central metabolism accompanies virulence activation in Pseudomonas aeruginosa. mBio 11, e02730–e02818 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  116. May, T. B. & Chakrabarty, A. M. Pseudomonas aeruginosa: genes and enzymes of alginate synthesis. Trends Microbiol. 2, 151–157 (1994).

    PubMed  CAS  Google Scholar 

  117. Chubukov, V., Gerosa, L., Kochanowski, K. & Sauer, U. Coordination of microbial metabolism. Nat. Rev. Microbiol. 12, 327–340 (2014).

    PubMed  CAS  Google Scholar 

  118. Singh, R., Mailloux, R. J., Puiseux-Dao, S. & Appanna, V. D. Oxidative stress evokes a metabolic adaptation that favors increased NADPH synthesis and decreased NADH production in Pseudomonas fluorescens. J. Bacteriol. 189, 6665–6675 (2007).

    PubMed  PubMed Central  CAS  Google Scholar 

  119. Bartell, J. A. et al. Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis. Nat. Commun. 8, ncomms14631 (2017).

    Google Scholar 

  120. Costerton, J. W. et al. Bacterial biofilms in nature and disease. Annu. Rev. Microbiol. 41, 435–464 (1987). This classical review paper underscores the importance of bacterial biofilms in natural environments as well as in disease.

    PubMed  CAS  Google Scholar 

  121. Jensen, P. Ø., Givskov, M., Bjarnsholt, T. & Moser, C. The immune system vs. Pseudomonas aeruginosa biofilms. Pathog. Dis. 59, 292 305 (2010).

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was funded by the Cystic Fibrosis Foundation (CFF) (grant number MOLIN18G0), the Cystic Fibrosis Trust (grant number Strategic Research Centre Award — 2019 — SRC 017), the Novo Nordisk Foundation Center for Biosustainability (CfB), Technical University of Denmark and The Novo Nordisk Foundation (NNF) (grant number NNF10CC1016517). J.A.B was funded by a postdoctoral fellowship from the Whitaker Foundation. H.K.J. was supported by NNF as a clinical research stipend (NNF12OC1015920), Rigshospitalets Rammebevilling 2015–17 (R88-A3537), Lundbeckfonden (R167-2013-15229), NNF (NNF15OC0017444), RegionH Rammebevilling (R144-A5287), Independent Research Fund Denmark/Medical and Health Sciences (FTP-4183-00051) and ‘Savværksejer Jeppe Juhl og Hustru Ovita Juhls mindelegat’.

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  1. Elio Rossi

    Present address: Department of Biosciences, Università degli Studi di Milano, Milan, Italy

Authors and Affiliations

  1. Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark

    Elio Rossi, Lea M. Sommer & Helle Krogh Johansen

  2. The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark

    Ruggero La Rosa, Jennifer A. Bartell, Janus A. J. Haagensen, Søren Molin & Helle Krogh Johansen

  3. Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark

    Rasmus L. Marvig

  4. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Helle Krogh Johansen

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  1. Elio Rossi
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All authors contributed to the text of the article. E.R., S.M. and H.K.J. wrote the final version and performed all of the necessary editing.

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Glossary

Clone type

Isolates of the same species that differ in their genomes by fewer than 10,000 single-nucleotide polymorphisms.

Hypermutator phenotype

A phenotype that shows an up to a 1,000-fold increased mutation rate compared with that of wild-type strains.

Expectorates

Cough or spit-out materials from the lower airways.

Bronchoalveolar lavage

A minimally invasive procedure that involves instillation of sterile saline into a segment of the lung, followed by suction and collection of the instillation for analysis. This procedure is typically facilitated by the introduction of a flexible bronchoscope into a segment of the lung.

Chronic obstructive pulmonary disease

A progressive lung disease that worsens over time, characterized by long-term breathing problems and poor airflow. The most common cause of chronic obstructive pulmonary disease is tobacco smoking, with a smaller number of cases due to factors such as air pollution and genetics.

Exacerbations

Worsening of chronic airway disease symptoms caused by a lung infection leading to increased production of secretion.

High-persister

A phenotype describing a substantial increase in the size of the surviving subpopulation during intensive antibiotic treatment without being resistant.

Tandem amplification

A process that occurs in DNA when a sequence of nucleotides is repeated and the repetitions are directly adjacent to each other. Changes in gene copy number are among the most frequent mutational events in all genomes.

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Rossi, E., La Rosa, R., Bartell, J.A. et al. Pseudomonas aeruginosa adaptation and evolution in patients with cystic fibrosis. Nat Rev Microbiol 19, 331–342 (2021). https://doi.org/10.1038/s41579-020-00477-5

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