Filamentous Bacteriophage Delay Healing of Pseudomonas-Infected Wounds

Bach, Michelle S.; Vries, Christiaan R. de; Sweere, Johanna M.; Popescu, Medeea; Belleghem, Jonas Van; Kaber, Gernot; Burgener, Elizabeth B.; Liú, Dan; Tran, Quynh-Lam; Dharmaraj, Tejas; Birukova, Maria; Sunkari, Vivekananda Gupta; Balaji, Swathi; Keswani, Sundeep G.; Banaei, Niaz; Khona, Dolly; Nedelec, Laurence; Sen, Chandan K.; Chandra, Venita; Secor, Patrick R.; Suh, Gina A.; Bollyky, Paul L.

doi:10.1101/2020.03.10.985663

Cited by 3 publications

(3 citation statements)

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“…We observed that less than 10% of children with CF who are infected with Pa have Pf+ strains, while over 40% of adults and 100% of 10 pre-lung transplant patients have Pf+ strains (7). The prevalence of Pf phages likewise increases over time in patients with chronic Pa wound infections (42). Together these data point to selective advantages for Pf+ Pa strains in the setting of chronic infection.…”

Section: Introductionmentioning

confidence: 64%

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

Pourtois

Kratochvil

Chen

et al. 2020

Preprint

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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.

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Section: Introductionmentioning

confidence: 64%

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

Pourtois

Kratochvil

Chen

et al. 2020

Preprint

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“…Filamentous phages infecting P. aeruginosa can physically interact with mammalian immune cells triggering a maladaptive immune response that results in impaired bacterial clearance during infections ( Sweere et al, 2019 ). These phages have been also involved in an immune response impairing keratinocyte migration and leading to delayed healing of P. aeruginosa -infected wounds ( Bach et al, 2020 ). Although filamentous phages do not represent a virus type selected for therapy purposes, these studies highlight the complex consequences of previously unknown interactions between phages and the immune system.…”

Section: Revisiting Phage Therapymentioning

confidence: 99%

Eco-Evolutionary Effects of Bacterial Cooperation on Phage Therapy: An Unknown Risk?

2020

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If there is something we have learned from the antibiotic era, it is that indiscriminate use of a therapeutic agent without a clear understanding of its long-term evolutionary impact can have enormous health repercussions. This knowledge is particularly relevant when the therapeutic agents are remarkably adaptable and diverse biological entities capable of a plethora of interactions, most of which remain largely unexplored. Although phage therapy (PT) undoubtedly holds the potential to save lives, its current efficacy in case studies recalls the golden era of antibiotics, when these compounds were highly effective and the possibility of them becoming ineffective seemed remote. Safe PT schemes depend on our understanding of how phages interact with, and evolve in, highly complex environments. Here, we summarize and review emerging evidence in a commonly overlooked theme in PT: bacteria-phage interactions. In particular, we discuss the influence of quorum sensing (QS) on phage susceptibility, the consequent role of phages in modulating bacterial cooperation, and the potential implications of this relationship in PT, including how we can use this knowledge to inform PT strategies. We highlight that the influence of QS on phage susceptibility seems to be widespread but can have contrasting outcomes depending on the bacterial host, underscoring the need to thoroughly characterize this link in various bacterial models. Furthermore, we encourage researchers to exploit competition experiments, experimental evolution, and mathematical modeling to explore this relationship further in relevant infection models. Finally, we emphasize that long-term PT success requires research on phage ecology and evolution to inform the design of optimal therapeutic schemes.

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“…Less than 10% of children with CF who are infected with Pa have Pf-positive (Pf+) strains, while over 40% of adults and 100% of 10 prelung transplant patients have Pf+ strains ( 7 , 26 ). The prevalence of Pf phages likewise increases over time in patients with chronic Pa wound infections ( 32 ). Of note, in a longitudinal cohort study of patients with CF, the acquisition of Pf phage represented the appearance of a new strain of Pa .…”

Section: Introductionmentioning

confidence: 99%

Filamentous Bacteriophages and the Competitive Interaction between Pseudomonas aeruginosa Strains under Antibiotic Treatment: a Modeling Study

et al. 2021

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Filamentous 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.

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Filamentous Bacteriophage Delay Healing of Pseudomonas-Infected Wounds

Cited by 3 publications

References 65 publications

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

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

Eco-Evolutionary Effects of Bacterial Cooperation on Phage Therapy: An Unknown Risk?

Filamentous Bacteriophages and the Competitive Interaction between Pseudomonas aeruginosa Strains under Antibiotic Treatment: a Modeling Study

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