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Pseudomonas aeruginosa rugose small-colony variants have adaptations that likely promote persistence in the cystic fibrosis lung.

ABSTRACT: Pseudomonas aeruginosa is recognized for its ability to colonize diverse habitats, ranging from soil to immunocompromised people. The formation of surface-associated communities called biofilms is one factor thought to enhance colonization and persistence in these diverse environments. Another factor is the ability of P. aeruginosa to diversify genetically, generating phenotypically distinct subpopulations. One manifestation of diversification is the appearance of colony morphology variants on solid medium. Both laboratory biofilm growth and chronic cystic fibrosis (CF) airway infections produce rugose small-colony variants (RSCVs) characterized by wrinkled, small colonies and an elevated capacity to form biofilms. Previous reports vary on the characteristics attributable to RSCVs. Here we report a detailed comparison of clonally related wild-type and RSCV strains isolated from both CF sputum and laboratory biofilm cultures. The clinical RSCV had many characteristics in common with biofilm RSCVs. Transcriptional profiling and Biolog phenotypic analysis revealed that RSCVs display increased expression of the pel and psl polysaccharide gene clusters, decreased expression of motility functions, and a defect in growth on some amino acid and tricarboxylic acid cycle intermediates as sole carbon sources. RSCVs also elicited a reduced chemokine response from polarized airway epithelium cells compared to wild-type strains. A common feature of all RSCVs analyzed in this study is increased levels of the intracellular signaling molecule cyclic di-GMP (c-di-GMP). To assess the global transcriptional effects of elevated c-di-GMP levels, we engineered an RSCV strain that had elevated c-di-GMP levels but did not autoaggregate. Our results showed that about 50 genes are differentially expressed in response to elevated intracellular c-di-GMP levels. Among these genes are the pel and psl genes, which are upregulated, and flagellum and pilus genes, which are downregulated. RSCV traits such as increased exopolysaccharide production leading to antibiotic tolerance, altered metabolism, and reduced immunogenicity may contribute to increased persistence in biofilms and in the airways of CF lungs.

SUBMITTER: Starkey M

PROVIDER: S-EPMC2681918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: During its persistence in cystic fibrosis (CF) airways, P. aeruginosa develops a series of phenotypic changes by the accumulation of pathoadaptive mutations. A better understanding of the role of these mutations in the adaptive process, with particular reference to the development of multidrug resistance (MDR), is essential for future development of novel therapeutic approaches, including the identification of new drug targets and the implementation of more efficient antibiotic therapy. Although several whole-genome sequencing studies on P. aeruginosa CF lineages have been published, the evolutionary trajectories in relation to the development of antimicrobial resistance remain mostly unexplored to date. In this study, we monitored the adaptive changes of P. aeruginosa during its microevolution in the CF airways to provide an innovative, genome-wide picture of mutations and persistent phenotypes and to point out potential novel mechanisms allowing survival in CF patients under antibiotic therapy. Results: We obtained whole genome sequences of 40 P. aeruginosa clinical CF strains isolated at Trentino Regional Support CF Centre (Rovereto, Italy) from a single CF patient over an 8-year period (2007-2014). Genotypic analysis of the P. aeruginosa isolates revealed a clonal population dominated by the Sequence Type 390 and three closely related variants, indicating that all members of the population likely belong to the same clonal lineage and evolved from a common ancestor. While the majority of early isolates were susceptible to most antibiotics tested, over time resistant phenotypes increased in the persistent population. Genomic analyses of the population indicated a correlation between the evolution of antibiotic resistance profiles and phylogenetic relationships, and a number of putative pathoadaptive variations were identified. Conclusion: This study provides valuable insights into the within-host adaptation and microevolution of P. aeruginosa in the CF lung and revealed the emergence of an MDR phenotype over time, which could not be comprehensively explained by the variations found in known resistance genes. Further investigations on uncharacterized variations disclosed in this study should help to increase our understanding of the development of MDR phenotype and the poor outcome of antibiotic therapies in many CF patients.

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Pseudomonas aeruginosa rugose small-colony variants have adaptations that likely promote persistence in the cystic fibrosis lung.

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