Filamentous bacteriophages and the competitive interaction between Pseudomonas aeruginosa strains under antibiotic treatment: A modeling study

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Julie D. Pourtois and Giulio A. De Leo, Hopkins Marine Station, Stanford University, Pacific Grove, CA, Julie D. Pourtois and Giulio A. De Leo, Department of Biology, Stanford University, Stanford, CA, Michael J. Kratochvil, Department of Materials Science and Engineering, Stanford University, Stanford, CA, Michael J. Kratochvil, Qingquan Chen, Naomi L. Haddock and Paul Bollyky, Department of Medicine, Stanford University, Stanford, CA, Elizabeth B. Burgener, Department of Pediatrics, Stanford University, Stanford, CA

Background/Question/Methods
Pseudomonas aeruginosa (Pa) is a major bacterial pathogen responsible for chronic lung infections in cystic fibrosis patients. Recent work has implicated Pf bacteriophages, filamentous viruses produced by Pa, in the chronicity and severity of Pa infections. Unlike many bacteriophages, these filamentous phages do not lyse their bacterial hosts. In addition, Pf phages influence biofilm formation and function; they 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 phage-positive (Pf+) bacteria increases over time in patients with cystic fibrosis, who are commonly maintained on cycled courses of inhaled antibiotics. 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 particular, we use our model to compare the fitness of Pf+ and Pf- strains in different competition settings when exposed to different concentrations of antibiotics and for a range of metabolic costs.
Results/Conclusions
Our model suggests that Pf+ strains of Pa cannot outcompete Pf- strains if the benefits of phage production fall onto both Pf+ and Pf- strains, or if these benefits are minimal. This is consistent with the low Pf phage prevalence in pediatric patients with CF, many of whom have received relatively limited antibiotic treatments. 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. In addition, high antibiotic sequestration, high antibiotic killing rates and low antibiotic decay rates particularly favored Pf+ strains in our model. Many other bacteria such as Escherichia coli, Klebsiella pneumonia, Neisseria meningitidis, and many Vibrio species are also infected by filamentous phages. Our results thus inform our understanding of bacterial competition in a wide range of contexts—including ecological systems in which bacteria produce anti-microbial compounds—as well as in the clinical setting we focus on in this work.