Allelic polymorphism shapes community function in evolving <i>Pseudomonas aeruginosa</i> populations

Azimi, Sheyda; Roberts, Aled Edward Lloyd; Peng, Shengyun; Weitz, Joshua S.; McNally, Alan; Brown, Samuel; Diggle, Stephen P.

doi:10.1101/644724

Cited by 6 publications

(8 citation statements)

References 93 publications

(139 reference statements)

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“…We have shown that, contrary to the trade-off hypothesis, virulence does not necessarily increase even when the restriction of transmission potential is removed. In fact, evolution was not reproducible in the three independent selection lines, in contrast to a previous study that showed P. aeruginosa evolution was highly reproducible in vitro [73], further highlighting the importance of factoring host-specific variables such as immune response in predictions of virulence. Our study also adds to the breadth of knowledge on P. aeruginosa adaptations in chronic wounds, showing that while P. aeruginosa employs similar adaptive strategies, i.e.…”

Section: Discussioncontrasting

confidence: 98%

The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection

Vanderwoude

Fleming

Azimi

et al. 2020

Preprint

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Idea: Evolution of virulence in general and testing of theory. Evolution of virulence can go in different directions. ABSTRACTOpportunistic pathogens are associated with several widespread, recalcitrant chronic infections in humans. As the pipeline for new antibiotics thins, virulence management presents an alternative solution to the rising antimicrobial resistance crisis in treating chronic infections. However, the nature of virulence in opportunists is not fully understood. The trade-off hypothesis has been a popular rationalization for the evolution of parasitic virulence since it was first proposed in the early 1980s, but whether it accurately models the evolutionary trajectories of opportunistic pathogens is still uncertain. Here, we tested the evolution of virulence in the human opportunist Pseudomonas aeruginosa PA14 in a murine chronic wound model. We found that in a serial passage experiment where transmission potential is no longer an epidemiological restriction, virulence does not necessarily increase as is predicted by the trade-off hypothesis, and in fact may evolve in different directions. We also assessed P. aeruginosa adaptations to a chronic wound after ten rounds of selection, and found that phenotypic heterogeneity in P. aeruginosa is limited in chronic wounds compared to heterogeneity seen in cystic fibrosis (CF) infections. Using whole genome sequencing, we found that genes coding for virulence factors thought to be crucial in P. aeruginosa pathogenesis acquired mutations during adaptation in chronic wounds. Our findings highlight that (i) current virulence models do not adequately explain the diverging evolutionary trajectories observed during P. aeruginosa chronic wound infection, (ii) P. aeruginosa phenotypic heterogeneity is less extensive in chronic wounds than in CF lungs, (iii) genes involved in P. aeruginosa virulence acquire mutations in chronic wounds, and (iv) similar adaptations are employed by P. aeruginosa both in a chronic wound and CF lung.

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Section: Discussioncontrasting

confidence: 98%

The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection

Vanderwoude

Fleming

Azimi

et al. 2020

Preprint

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“…The concept of population phenotype is related to the frequencies and distribution of relevant alleles in bacterial populations, which can shape community functions and influence clinical outcomes (Azimi et al, 2020). In this work, we demonstrate how the dynamics of multiple and changing antibiotic pressures, together with higher mutation rates, resulted in high allelic variations of the PDC β-lactamase in a diversified resistant clonal population that originally evolved from a susceptible ancestral infecting strain.…”

Section: Discussionmentioning

confidence: 99%

Development of antibiotic resistance reveals diverse evolutionary pathways to face the complex and dynamic environment of a long-term treated patient

Colque

Tomatis

Orio

et al. 2021

Preprint

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Bacteria are endowed with a unique ability to adapt to challenging environments. The evolution of bacterial populations during chronic infections involves a large diversity of adaptive mechanisms that cannot always be reproduced upon controlled laboratory conditions. This creates a gap between the phenotypical description and the underlying biochemical processes that drive that phenotype. Herein, we address the complexity of the bacterial adaptive response to antibiotic selective pressures by studying the in-patient evolution of a broad diversity of β-lactam resistant Pseudomonas aeruginosa hypermutator clones. By using mutational and ultra-deep amplicon sequencing analysis, we analyzed multiple generations of a P. aeruginosa hypermutator strain persisting for more than 26 years of chronic infection in the airways of a cystic fibrosis patient. We identify the accumulation of multiple alterations targeting the chromosomally encoded class C β-lactamase (blaPDC), providing structural and functional protein changes that resulted in a continuous enhancement of its catalytic efficiency and high level of cephalosporin resistance. This evolution was linked to the persistent treatment with ceftazidime, which we demonstrate selected for variants with robust catalytic activity against this expanded-spectrum cephalosporin. Surprisingly, 'a gain of function' of collateral resistance towards ceftolozane, a more recently introduced cephalosporin that was not prescribed to this patient, was also observed and the biochemical basis of this cross-resistance phenomenon was elucidated. This work pinpoints the considerable evolutionary potential of hypermutator strains and uncovers the link between the antibiotic prescription history and the in-patient evolution of resistance.

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“…The nutritional environment is increasingly appreciated as a major selective pressure, which motivated development of an artificial sputum medium that approximates concentrations found in patients with CF and produces similar growth phenotypes and transcriptional responses as actual sputum (20)(21)(22). Evolution experiments with P. aeruginosa have been conducted in this medium to identify beneficial mutations in particular conditions, including antibiotic pressure (23), biofilm lifestyle (24), and presence of mucins (23,25). Several observations are consistent across these studies, particularly the rapid diversification of biofilm, motility, and colony phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…Several observations are consistent across these studies, particularly the rapid diversification of biofilm, motility, and colony phenotypes. Mutations in certain genes have also been identified repeatedly including lasR, wsp, and flagella synthesis genes (23,24,26,27).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, the lasR gene encodes the transcriptional regulator of the LasRI acyl-homoserine lactone (AHL) quorum sensing system which regulates the expression of hundreds of genes, including other quorum sensing systems (RhlRI and PQS). Loss-of-function lasR mutations reduce production of extracellular proteases (28), improve fitness in microoxia (29), increase resistance to ceftazidime (24), improve growth in amino acids (30), and produce a "lysis and sheen" colony morphology (30). LasR mutants are frequently described as social cheaters because they can use public goods such as proteases produced by competitors without undergoing the cost of producing these products themselves (31,32), although recent findings suggest that lasR mutants actually overproduce these public goods when co-cultured with a LasR+ strain (33).…”

Section: Introductionmentioning

confidence: 99%

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The nutritional environment is sufficient to select coexisting biofilm and quorum-sensing mutants of Pseudomonas aeruginosa

Scribner

Stephens

Huong

et al. 2021

Preprint

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The evolution of bacterial populations during infections can be influenced by various factors including available nutrients, the immune system, and competing microbes, rendering it difficult to identify the specific forces that select on evolved traits. The genomes of Pseudomonas aeruginosa isolated from the airway of patients with cystic fibrosis (CF), for example, have revealed commonly mutated genes, but which phenotypes led to their prevalence is often uncertain. Here, we focus on effects of nutritional components of the CF airway on genetic adaptations by P. aeruginosa grown in either well-mixed (planktonic) or biofilm-associated conditions. After only 80 generations of experimental evolution in a simple medium with glucose, lactate, and amino acids, all planktonic populations diversified into lineages with mutated genes common to CF infections: morA, encoding a regulator of biofilm formation, or lasR, encoding a quorum sensing regulator that modulates the expression of virulence factors. Although mutated quorum sensing is often thought to be selected in vivo due to altered virulence phenotypes or social cheating, isolates with lasR mutations demonstrated increased fitness when grown alone and outcompeted the ancestral PA14 strain. Nonsynonymous SNPs in morA increased fitness in a nutrient concentration-dependent manner during planktonic growth and surprisingly also increased biofilm production. Populations propagated in biofilm conditions also acquired mutations in loci associated with chronic infections, including lasR and cyclic-di-GMP regulators roeA and wspF. These findings demonstrate that nutrient conditions and biofilm selection are alone sufficient to select mutants with problematic clinical phenotypes including increased biofilm and altered quorum sensing.

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Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations

Cited by 6 publications

References 93 publications

The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection

The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection

Development of antibiotic resistance reveals diverse evolutionary pathways to face the complex and dynamic environment of a long-term treated patient

The nutritional environment is sufficient to select coexisting biofilm and quorum-sensing mutants of Pseudomonas aeruginosa

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