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.

Keywords: airway epithelium; antimicrobial resistance; bacteriophage; cystic fibrosis; mucus.

Figure 1

According to the Australian Cystic Fibrosis Data Registry 2020 (ACFDR 2020) (64), common microorganisms found in the respiratory tracts of individuals with CF, including the most common pathogen in early childhood S. aureus, and the most common pathogens in adulthood P. aeruginosa. Currie and colleagues reported the selection of intravenous primary and secondary inhaled or intravenous antibiotics by pediatrics or adult physicians across multiple CF centers in Australia (52). The susceptibility of a few common antibiotics (CAZ = ceftazimide; PIP/TAZ = piperacillin-tazobactam; TOB = tobramycin; COL = colistin; MER = meropenem; CIP = ciprofloxacin; VAN = vancomycin) of the common pathogens recovered from CF lung (60–63). √ indicates susceptibility, +/− indicates partial susceptibility, − indicates resistant and NR indicates not reported. For example, S. aureus typically exhibits multi-drug resistance, across most antibiotics including macrolides (55, 65). Furthermore, the MRSA strain confers resistance to β-lactams, quinolones and aminoglycosides (55, 65). The prominent CF pathogen, P. aeruginosa, also is developing broad spectrum resistance and other less common pathogens, including BCC, are resistant to most of the β-lactams, aminoglycosides, and cationic antimicrobial peptides (66). Created with BioRender.com.

Figure 2

Schematic representation of the tripartite (phage-bacteria-epithelial cells) of CF epithelium is characterized by low airway surface liquid and thick and dense mucus containing mucus flakes and hyperconcentrated mucins. In CF, commensal bacteria and phage communities are dysregulated following long-term pathogenic chronic bacterial infection with dominant species and limited phages. (1) In addition, glycans that form mucins can also regulate the adhesion of P. aeruginosa. It is unknown if CF mucus flakes constitute a different glycan profile which could stimulate biofilm formation. (2) Phages can adhere to mucin directly; it is unknown how or if phages bind to CF mucus flakes directly and if their capsid proteins are subseqeuntly altered. Adherence of phage to CF mucus may facilitate phage enrichment and persistence within the microenvironment, resulting in a potent phage phenotype or vice versa. (3) Previous studies identified that certain phages, but not all, bind to mucins and diminish bacterial killing activity. Of concern, it is unknown if the binding activity of phages to mucin is a generic feature or size and structure dependent. (4) Importantly, if CF mucus results in the emergence of phage resistance which contradicts the theory of virulence enhancement by mucus, other therapeutic strategies might need to be applied in conjunction with the proposed phage therapy in CF. Created with BioRender.com.