The Impact of Pf Bacteriophages on the Fitness ofPseudomonas aeruginosa; A Mathematical Modeling Approach

Abstract

Pseudomonas aeruginosa (Pa) is a major bacterial pathogen responsible for chronic lung infections in cystic fibrosis patients. Recent work by ourselves and others has implicated Pf bacteriophages, non-lytic filamentous viruses produced by Pa, in the chronicity and severity of Pa infections. Pf phages act as structural elements in Pa biofilms and sequester aerosolized antibiotics, thereby contributing to antibiotic tolerance. Consistent with a selective advantage in this setting, the prevalence of Pf+ bacteria increases over time in these patients. However, the production of Pf phages comes at a metabolic cost to bacteria, such that Pf+ strains grow more slowly than Pf- strains in vitro. Here, we use a mathematical model to investigate how these competing pressures might influence the relative abundance of Pf+ versus Pf- strains in different settings. Our model predicts that Pf+ strains of Pa can only outcompete Pf- strains if the benefits of phage production falls solely onto Pf+ strains and not onto the overall bacterial community in the lung. Further, phage production only leads to a net positive gain in fitness at antibiotic concentrations slightly above the minimum inhibitory concentration (i.e., concentrations for which the benefits of antibiotic sequestration outweigh the metabolic cost of phage production), but which are not lethal for Pf+ strains. As a result, our model predicts that frequent administration of intermediate doses of antibiotics with low decay rates favors Pf+ over Pf- strains. These models inform our understanding of the ecology of Pf phages and suggest potential treatment strategies for Pf+ Pa infections.ImportanceFilamentous phages are a frontier in bacterial pathogenesis, but the impact of these phages on bacterial fitness is unclear. In particular, Pf phages produced by Pa promote antibiotic tolerance but are metabolically expensive to produce, suggesting that competing pressures may influence the prevalence of Pf+ versus Pf- strains of Pa in different settings. Our results identify conditions likely to favor Pf+ strains and thus antibiotic tolerance. This study contributes to a better understanding of the unique ecology of filamentous phages and may facilitate improved treatment strategies for combating antibiotic tolerance.

Homogenization modelling of antibiotic diffusion and adsorption in viral liquid crystals

“…Formation of liquid crystals has also been studied for other biofilms than P. aeruginosa [9,10]. However, the topic is relatively novel and mathematical modelling of liquid crystalline biofilms has been limited to cell-level simulations [9,10] and population dynamics [11].…”

Modelling of filamentous phage-induced antibiotic tolerance of P. aeruginosa

“…While, in general, the mathematical modelling of biological liquid crystals is a well-explored topic [ 10 ], for biofilms the models are limited. As this is a relatively new area, the mathematical approaches developed so far mainly concern global population dynamics [ 11 ] and empirical fitting models [ 12 – 17 ], with some recent, pioneering work also including cell-level simulations [ 3 , 4 ]. To the best of our knowledge, no continuum models describing liquid crystalline order in biofilms exist.…”

Modelling of filamentous phage-induced antibiotic tolerance of P.aeruginosa

“…While, in general, the mathematical modelling of biological liquid crystals is a well-explored topic [10], for biofilms the models are limited. As this a relatively new area, the mathematical approaches developed so far mainly concern global population dynamics [11] and empirical fitting models [12][13][14][15][16][17], with some recent, pioneering work also including cell-level simulations [3,4]. To the best of our knowledge, no continuum models describing liquid crystalline order in biofilms exist.…”