The Challenging Life of Mutators: How Pseudomonas aeruginosa Survives between Persistence and Evolution in Cystic Fibrosis Lung

Abstract

Cystic fibrosis (CF) is a life-threatening genetic disease characterised by chronic lung infections sustained by opportunistic pathogens such as Pseudomonas aeruginosa. During the chronic long-lasting lung infections, P. aeruginosa adapts to the host environment. Hypermutability, mainly due to defects in the DNA repair system, resulting in an increased spontaneous mutation rate, represents a way to boost the rapid adaptation frequently encountered in CF P. aeruginosa isolates. We selected 609 isolates from 51 patients with CF chronically colonised by P. aeruginosa to study, by full-length genome sequencing, the longitudinal evolution of the bacterium. We recovered at least one hypermutable (mutator) isolate in 57% of patients. By combining genomic information and phenotypic analyses, we followed the evolutionary pathways of the P. aeruginosa mutator strains, identifying their contribution to multi-drug resistance and the emergence of new sub-lineages. By implementing patient clinical data, we observed that mutators preferentially follow a specific evolutionary trajectory in patients with a negative clinical outcome and that maintenance antibiotic polytherapy, based on alternating molecules, apparently reduces the occurrence of hypermutability. Finally, we draw attention to the possibility that modulator-induced changes in the pulmonary environment may be associated with the onset of hypermutability.

Keywords: Pseudomonas aeruginosa; cystic fibrosis; evolution; hypermutability; modulator; multi-drug resistance; whole-genome sequencing.

Figure 1

The mutations in the resistome (resistance-associated genes) identified via whole-genome sequencing and bioinformatics analysis for the 70 mutator Pseudomonas aeruginosa. Mutator genes involved and typology of mutations (missense, nucleotides insertions/deletions, or stop) are shown in different colours and are reported in the legend.