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

• DOI: 10.1164/rccm.200812-1943oc
• Publication Date: 2009-05-08T01:25:05Z
• Authors: Alessandra Bragonzi; Moira Paroni; Alessandro Nonis; Nina Cramer; Sara Montanari; Joanna Rejman; Clelia Di Serio; Gerd Döring; Burkhard Tümmler
• Keywords: Male; 0301 basic medicine; Cystic Fibrosis; Virulence; Clone Cells; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Chronic Disease; Pseudomonas aeruginosa; respiratory tract infections ; Pseudomonas infection ; biological adaptation ; cystic fibrosis; Animals; Humans; Mice, Inbred CFTR; Pseudomonas Infections; Respiratory Tract Infections

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