Pulmonary bacteriophage and cystic fibrosis airway mucus: friends or foes?

Abstract

For those born with cystic fibrosis (CF), hyper-concentrated mucus with a dysfunctional structure significantly impacts CF airways, providing a perfect environment for bacterial colonization and subsequent chronic infection. Early treatment with antibiotics limits the prevalence of bacterial pathogens but permanently alters the CF airway microenvironment, resulting in antibiotic resistance and other long-term consequences. With little investment into new traditional antibiotics, safe and effective alternative therapeutic options are urgently needed. One gathering significant traction is bacteriophage (phage) therapy. However, little is known about which phages are effective for respiratory infections, the dynamics involved between phage(s) and the host airway, and associated by-products, including mucus. Work utilizing gut cell models suggest that phages adhere to mucus components, reducing microbial colonization and providing non-host-derived immune protection. Thus, phages retained in the CF mucus layer result from the positive selection that enables them to remain in the mucus layer. Phages bind weakly to mucus components, slowing down the diffusion motion and increasing their chance of encountering bacterial species for subsequent infection. Adherence of phage to mucus could also facilitate phage enrichment and persistence within the microenvironment, resulting in a potent phage phenotype or vice versa. However, how the CF microenvironment responds to phage and impacts phage functionality remains unknown. This review discusses CF associated lung diseases, the impact of CF mucus, and chronic bacterial infection. It then discusses the therapeutic potential of phages, their dynamic relationship with mucus and whether this may enhance or hinder airway bacterial infections in CF.

Involvement of Pf-like phages in resistance to phage infection in clinical isolates of P. aeruginosa from cystic fibrosis patients

“…The great diversity of anti-phage defence systems found in the Pf-like phages identified may be a result of the co-existence of bacterial and phages in CF mucus, as recently demonstrated in a study conducted in the fish pathogen Flavobacterium columnare, in which co-existence with a predatory phage was involved in the development of phage resistance, in particular by the acquisition of CRISPR-Cas immunity (31,32). Both lytic and lysogenic phages are ubiquitous in the body and therefore in the lungs of people suffering from CF.…”

“…The mucus in the lungs of CF patients is hyper-concentrated and has a unique structure that favours bacterial colonization and, as also occurs in gut mucosa, the phages bind to the mucus. The mucus creates spatial refuges that favour the coexistence between phages and bacteria, which can explain the coevolution of both (32)(33)(34).…”

Marine bacteriophages disturb the associated microbiota of Aurelia aurita with a recoverable effect on host morphology

“…This dynamic interplay between phages and bacteria in the gut microbiome can influence overall gut health and homeostasis ( Shkoporov and Hill, 2019 ; Li et al, 2021 ). Research in human individuals with cystic fibrosis ( CF ) investigated the impact of bacteriophages on the lung microbiome ( Kiedrowski and Bomberger, 2018 ; Ling et al, 2023 ). Phage-bacterial interactions contributed to the dynamics of bacterial populations in the CF lung, potentially influencing disease progression ( Megremis et al, 2023 ).…”

The Citizen Phage Library: Rapid Isolation of Phages for the Treatment of Antibiotic Resistant Infections in the UK

“…When utilising phages for phage therapy, there will be multiple environmental factors operating in vivo which may affect the activity of a phage against its target host. These include temperature and pH [ 57 ], the presence of biological materials such as mucus [ 58 , 59 ], host immune responses and the interaction with the host microbiome [ 57 , 60 ]. Additionally, bacteria within an infection may be present as biofilms or may exhibit altered phenotypes which may hinder the adsorption of the phage to the bacterial surface [ 61 ].…”