Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections

Abstract

Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification.

Keywords: Pseudomonas aeruginosa; adaptation; cystic fibrosis; evolution; population biology.

Figure 1

Pathoadaptive Mutations in Pseudomonas aeruginosa. Genes encoding regulatory proteins are highlighted in red. Genes encoding sigma factors are highlighted in blue.

Figure 2

Key Figure: Phenotypic Heterogeneity within Pseudomonas aeruginosa Populations in Cystic Fibrosis (CF) The figure shows a population structure based on 15 variable traits using the eBURST algorithm . From ten patients infected with the Liverpool epidemic strain (LES) of P. aeruginosa, 1720 isolates from 43 different sputum samples were analysed, giving rise to 398 unique ‘subtypes’ of the LES. Each sphere represents a different subtype. The size reflects the relative abundance of each subtype. Two subtypes connected by a single line differ in only one characteristic. The pie chart inset indicates the percentage contribution to diversity of variation between patients, between samples or within samples, demonstrating the major contribution of the latter. Adapted from .

Figure 3

Variations in the Antimicrobial Susceptibilities of Pseudomonas aeruginosa within Individual Patients. The figure summarises, for four antibiotics, the spread of zone of inhibition data (ZOI) in mm for multiple isolates taken from 13 patients infected with the Liverpool epidemic strain (LES). For each patient, a minimum of 80 isolates was analysed, taken at multiple sampling points (40 isolates per sample point). The red line indicates the recognised cut-off points as defined by the British Society for Antimicrobial Susceptibility . Note the tendency for isolates from the same patient to occur both above (susceptible) and below (resistant) the red line. Data adapted from two studies , .

Figure 4

Within-patient Variations in the Prevalence and Location within a Gene of Common Pathoadaptive Mutations. Based on sets of 40 isolates from a single sputum sample, for each of nine patients infected with the Liverpool epidemic strain, the prevalence and location of mutations is indicated for the lasR and mucA genes (with location relative to amino acid position on the predicted protein sequence indicated on the scale). Each patient is represented by the space between lines. Each circle represents the location of a mutation that is either severe (red; e.g., a frame-shift), a nonsynonymous single nucleotide polymorphism (orange; e.g., a single amino acid change), or a change that would not impact on the protein sequence (green). The size of the circle reflects the relative abundance in each set of 40 isolates (e.g., the severe lasR mutation in patient 9 was present in all 40 isolates tested). Analysis of data from a published study .