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Pseudomonas aeruginosa Microevolution during Cystic Fibrosis Lung Infection Establishes Clones with Adapted Virulence

¹ Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy; ² University Centre of Statistics for Biomedical Sciences, Vita-Salute S. Raffaele University, Milano, Italy; ³ Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany; and ⁴ Institute of Medical Microbiology and Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany

Correspondence and requests for reprints should be addressed to Alessandra Bragonzi, Ph.D., Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy. E-mail: bragonzi.alessandra{at}hsr.it

Rationale: During long-term lung infection in patients with cystic fibrosis (CF), Pseudomonas aeruginosa strains develop mutations leading to clonal expansion. This microevolution is believed to be correlated with a reduced virulence.

Objectives: We tested this hypothesis in models of lung infection, using mice with different genetic backgrounds.

Methods: From infected airways of six patients with CF, 25 P. aeruginosa clones were isolated during a period of up to 16.3 years and genotypically and phenotypically characterized. Virulence of the 8 early, 6 intermediate, and 11 late CF isolates and 5 environmental strains was assessed by monitoring acute mortality versus survival and P. aeruginosa chronic persistence versus lung clearance in mice of different genetic backgrounds, including CF mice.

Measurements and Main Results: Different patients harbored clonally unrelated strains, but early, intermediate, and late P. aeruginosa isolates from single patients were clonally related, allowing comparative in vivo analysis. Although late isolates were attenuated in causing acute mortality in the mouse models, compared with early and intermediate clonal isolates and environmental strains, they did not differ from early and intermediate clonal isolates in their capacity to establish chronic infection and cause extensive inflammation in the murine respiratory tract.

Conclusions: Our findings indicate that clonal expansion of P. aeruginosa strains during microevolution within CF lungs leads to populations with altered but not reduced virulence. These P. aeruginosa clones with adapted virulence play a critical role in the pathogenesis of chronic infections and may serve to define virulence determinants as targets for novel therapies.

Key Words: respiratory tract infections • Pseudomonas infection • biological adaptation • cystic fibrosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject During long-term lung infection in cystic fibrosis (CF), Pseudomonas aeruginosa strains develop numerous mutations. This bacterial microevolution is believed to be correlated with a reduction in P. aeruginosa virulence; however, this hypothesis has not been tested in vivo. What This Study Adds to the Field P. aeruginosa microevolution during chronic CF lung infection leads to altered but not reduced virulence.

 

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