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.
Temperate phages drive genomic diversification in bacterial pathogens. Phage-derived sequences are more common in pathogenic than nonpathogenic taxa and are associated with changes in pathogen virulence. High abundance and mobilization of temperate phages within hosts suggests that temperate phages could promote withinhost evolution of bacterial pathogens. However, their role in pathogen evolution has not been experimentally tested. We experimentally evolved replicate populations of Pseudomonas aeruginosa with or without a community of three temperate phages active in cystic fibrosis (CF) lung infections, including the transposable phage, ɸ4, which is closely related to phage D3112. Populations grew as freefloating biofilms in artificial sputum medium, mimicking sputum of CF lungs where P. aeruginosa is an important pathogen and undergoes evolutionary adaptation and diversification during chronic infection. Although bacterial populations adapted to the biofilm environment in both treatments, population genomic analysis revealed that phages altered both the trajectory and mode of evolution. Populations evolving with phages exhibited a greater degree of parallel evolution and faster selective sweeps than populations without phages. Phage ɸ4 integrated randomly into the bacterial chromosome, but integrations into motility-associated genes and regulators of quorum sensing systems essential for virulence were selected in parallel, strongly suggesting that these insertional inactivation mutations were adaptive. Temperate phages, and in particular transposable phages, are therefore likely to facilitate adaptive evolution of bacterial pathogens within hosts.Pseudomonas aeruginosa | cystic fibrosis | mobile genetic element | experimental evolution | bacteriophage C omparative genomics suggests that temperate phages play an important role in the evolution and genomic diversification of bacterial pathogens (1). Bacterial genomes often contain a range of intact and remnant prophage elements (1-3), and ecologically important bacterial traits are believed to be phage-derived (e.g., phage-derived bacteriocins) (4). Phage-related sequences are observed more frequently in pathogenic than nonpathogenic strains (5), and prophage acquisition can be associated with changes in pathogen virulence (6, 7). Prophages can directly contribute accessory gene functions (1, 8) or disrupt bacterial genes by insertional inactivation. Of particular note are the transposable class of temperate phages (also known as mutator phages), including D3112 of Pseudomonas aeruginosa (9, 10), which integrate throughout the chromosome disrupting existing genes and increasing the supply of mutations available to selection. Recent reports of high rates of phage mobilization within hosts (11) and high temperate phage abundance in humans (12), including at sites of chronic infection where phage particles have been observed to exceed bacterial host densities by 10-to 100-fold (13), suggests that temperate phages could play an important role in driving within-host...
Pseudomonas aeruginosa is a major pathogen in the lungs of cystic fibrosis (CF) patients. However, it is now recognised that a diverse microbial community exists in the airways comprising aerobic and anaerobic bacteria as well as fungi and viruses. This rich soup of microorganisms provides ample opportunity for interspecies interactions, particularly when considering secreted compounds. Here, we discuss how P. aeruginosa-secreted products can have community-wide effects, with the potential to ultimately shape microbial community dynamics within the lung. We focus on three well-studied traits associated with worsening clinical outcome in CF: phenazines, siderophores and biofilm formation, and discuss how secretions can shape interactions between P. aeruginosa and other commonly encountered members of the lung microbiome: Staphylococcus aureus, the Burkholderia cepacia complex, Candida albicans and Aspergillus fumigatus. These interactions may shape the evolutionary trajectory of P. aeruginosa while providing new opportunities for therapeutic exploitation of the CF lung microbiome.
Some microbial public goods can provide both individual and community‐wide benefits, and are open to exploitation by non‐producing species. One such example is the production of metal‐detoxifying siderophores. Here, we investigate whether conflicting selection pressures on siderophore production by heavy metals – a detoxifying effect of siderophores, and exploitation of this detoxifying effect – result in a net increase or decrease. We show that the proportion of siderophore‐producing taxa increases along a natural heavy metal gradient. A causal link between metal contamination and siderophore production was subsequently demonstrated in a microcosm experiment in compost, in which we observed changes in community composition towards taxa that produce relatively more siderophores following copper contamination. We confirmed the selective benefit of siderophores by showing that taxa producing large amounts of siderophore suffered less growth inhibition in toxic copper. Our results suggest that ecological selection will favour siderophore‐mediated decontamination, with important consequences for potential remediation strategies.
Bacteria are often iron-limited, and hence produce extracellular iron-scavenging siderophores. A crucial feature of siderophore production is that it can be an altruistic behaviour (individually costly but benefitting neighbouring cells), thus siderophore producers can be invaded by non-producing social ‘cheats’. Recent studies have shown that siderophores can also bind other heavy metals (such as Cu and Zn), but in this case siderophore chelation actually reduces metal uptake by bacteria. These complexes reduce heavy metal toxicity, hence siderophore production may contribute to toxic metal bioremediation. Here, we show that siderophore production in the context of bioremediation is also an altruistic trait and can be exploited by cheating phenotypes in the opportunistic pathogen Pseudomonas aeruginosa. Specifically, we show that in toxic copper concentrations (i) siderophore non-producers evolve de novo and reach high frequencies, and (ii) producing strains are fitter than isogenic non-producing strains in monoculture, and vice versa in co-culture. Moreover, we show that the evolutionary effect copper has on reducing siderophore production is greater than the reduction observed under iron-limited conditions. We discuss the relevance of these results to the evolution of siderophore production in natural communities and heavy metal bioremediation.
Cooperation in nature is ubiquitous, but is susceptible to social cheats who pay little or no cost of cooperation yet reap the benefits. The effect such cheats have on reducing population productivity suggests that there is selection for cooperators to mitigate the adverse effects of cheats. While mechanisms have been elucidated for scenarios involving a direct association between producer and cooperative product, it is less clear how cooperators may suppress cheating in an anonymous public goods scenario, where cheats cannot be directly identified. Here, we investigate the real-time evolutionary response of cooperators to cheats when cooperation is mediated by a diffusible public good: the production of iron-scavenging siderophores by Pseudomonas aeruginosa. We find that siderophore producers evolved in the presence of a high frequency of non-producing cheats were fitter in the presence of cheats, at no obvious cost to population productivity. A novel morphotype independently evolved and reached higher frequencies in cheat-adapted versus control populations, exhibiting reduced siderophore production but increased production of pyocyanin-an extracellular toxin that can also increase the availability of soluble iron. This suggests that cooperators may have mitigated the negative effects of cheats by downregulating siderophore production and upregulating an alternative iron-acquisition public good. More generally, the study emphasizes that cooperating organisms can rapidly adapt to the presence of anonymous cheats without necessarily incurring fitness costs in the environment they evolve in.
Background Pseudomonas aeruginosa typically displays loss of virulence-associated secretions over the course of chronic cystic fibrosis infections. This has led to the suggestion that virulence is a costly attribute in chronic infections. However, previous reports suggest that overproducing (OP) virulent pathotypes can coexist with non-producing mutants in the CF lung for many years. The consequences of such within-patient phenotypic diversity for the success of this pathogen are not fully understood. Here, we provide in-depth quantification of within-host variation in the production of three virulence associated secretions in the Liverpool cystic fibrosis epidemic strain of P. aeruginosa, and investgate the effect of this phenotypic variation on virulence in acute infections of an insect host model.ResultsWithin-patient variation was present for all three secretions (pyoverdine, pyocyanin and LasA protease). In two out of three patients sampled, OP isolates coexisted with under-producing mutants. In the third patient, all 39 isolates were under-producers of all three secretions relative to the transmissible ancestor LESB58. Finally, this phenotypic variation translated into variation in virulence in an insect host model.ConclusionsWithin population variation in the production of P. aeruginosa virulence-associated secretions can lead to high virulence sub-populations persisting in patients with chronic CF infections.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-017-0941-6) contains supplementary material, which is available to authorized users.
The respiratory tract is a compartmentalised and heterogenous environment. The nasopharynx and sinuses of the upper airways have distinct properties from the lungs and these differences may shape bacterial adaptation and evolution. Upper airway niches act as early colonisation sites for respiratory bacterial pathogens, including those, such as Pseudomonas aeruginosa, that can go on to establish chronic infection of the lungs in people with cystic fibrosis (CF). Despite the importance of upper airway environments in facilitating early adaptation to host environments, currently available in vitro models for study of respiratory infection in CF focus exclusively on the lungs. Furthermore, animal models, widely used to bridge the gap between in vitro systems and the clinical scenario, do not allow the upper and lower airways to be studied in isolation. We have developed a suite of culture media reproducing key features of the upper and lower airways, for the study of bacterial adaptation and evolution in different respiratory environments. For both upper and lower airway-mimicking media, we have developed formulations that reflect airway conditions in health and those that reflect the altered environment of the CF respiratory tract. Here, we describe the development and validation of these media and their use for study of genetic and phenotypic adaptations in P. aeruginosa during growth under upper or lower airway conditions in health and in CF.
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