Diversity of metabolic profiles of cystic fibrosis Pseudomonas aeruginosa during the early stages of lung infection

Abstract

Pseudomonas aeruginosa is the dominant pathogen infecting the airways of cystic fibrosis (CF) patients. During the intermittent colonization phase, P. aeruginosa resembles environmental strains but later evolves to the chronic adapted phenotype characterized by resistance to antibiotics and mutations in the global regulator genes mucA, lasR and rpoN. Our aim was to understand the metabolic changes occurring over time and between niches of the CF airways. By applying Phenotype MicroArrays, we investigated changes in the carbon and nitrogen catabolism of subsequently clonally related mucoid and non-mucoid (NM) lung and sinus P. aeruginosa isolates from 10 CF patients (five intermittently colonized/five chronically infected). We found the most pronounced catabolic changes for the early/late NM isolate comparisons, with respiratory reduction seen for all chronically infecting isolates and two intermittently colonizing isolates. Fewer differences were observed between sinus and lung isolates, showing a higher degree of isolate similarity between these two niches. Modest respiratory changes were seen for the early isolate/PAO1 comparisons, indicating colonization with environmental isolates. Assignment of metabolic pathways via the KEGG database showed a prevalence of substrates involved in the metabolism of Ala, Asp and Glu, D-Ala, and Arg and Pro. In conclusion, extensive heterogeneity in the metabolic profiles of the P. aeruginosa isolates was observed from the initial stages of the infection, showing a rapid diversification of the bacteria in the heterogeneous environment of the lung. Metabolic reduction seems to be a common trait and therefore an adaptive phenotype, though it can be reached via multiple metabolic pathways.

Generalized Growth of Estuarine, Household and Clinical Isolates of Pseudomonas aeruginosa

“…Overall differences in P. aeruginosa growth among media types depended on the habitat of origin (Origin ∗ Media effect, Table 2B ); this was driven in part by poorer growth of household P. aeruginosa on big bluestem leachate than on the other two media ( Figures 1D – F , p < 0.001 for both contrasts after correction for multiple comparisons), and by marginally significantly higher growth of estuary isolates than household isolates on big bluestem leachate ( p = 0.08 after correction for multiple comparisons). There were also significant differences among isolates within habitats of origin in their overall and media-specific growth (Isolate(Origin) [mean] and Isolate ∗ Media(Origin) [mean] effects, Table 2B ), consistent with other studies showing metabolic diversity among P. aeruginosa ( Palmer et al, 2010 ; Rodríguez-Rojas et al, 2012 ; Jørgensen et al, 2015 ). However, the model also indicated that habitats of origin differed in isolate to isolate variability in the dependence of growth on media type (Isolate ∗ Media(Origin) [variance] effect, Table 2B ), with household isolates being substantially more variable in their media-specific response, and isolates from the estuary and the clinical isolates being more consistent with others from their habitat of origin.…”

The Pseudomonas aeruginosa Complement of Lactate Dehydrogenases Enables Use of d - and l -Lactate and Metabolic Cross-Feeding

“…We found that H. influenzae and S. maltophilia contain an l -lactate dehydrogenase homolog but that A. xylosoxidans and B. multivorans , like P. aeruginosa , contain multiple homologs. As l -lactate is a significant metabolite available in the lungs of CF patients ( 11 , 25 , 36 , 37 ), these enzymes may contribute to the abilities of P. aeruginosa and other pathogens to colonize and persist in this environment.…”

The phenotypic evolution of Pseudomonas aeruginosa populations changes in the presence of subinhibitory concentrations of ciprofloxacin

“…Few biologically significant changes [defined in accordance with Jørgensen et al (2015) as differences in areas of the two respiration curves of more than 20 000 software units] in substrate catabolism of PAO1 and DmutS evolved populations compared to ancestor populations were observed (Fig. S2).…”