The changing landscape of the cystic fibrosis lung environment: From the perspective of Pseudomonas aeruginosa

Abstract

This review guides the reader through the current understanding of the dynamic changes that occur within the cystic fibrosis (CF) lung that allow Pseudomonas aeruginosa to become the dominant pathogen associated with CF. Although recent studies provide some insight, the mechanisms that drive the changing landscape of the lung environment throughout an individual's lifetime that prime P. aeruginosa to take over and establish chronic infection within the lungs, remain poorly understood. We explore how the CF lung environment shapes the ability of P. aeruginosa to persist in spite of intense antimicrobial therapy. We also highlight the pioneering use of a triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, Trikafta, to restore CFTR function and how it influences P. aeruginosa persistence in the CF lung. We utilize existing data for single modulator therapies to extrapolate the potential future of pathogen infection in the era of Trikafta therapy.

Figure 1. Progression of cystic fibrosis lung disease.

Key evolutionary steps involved in the progression of cystic fibrosis lung disease starting at birth. Initial ion imbalance leads to airway mucus accumulation and stagnation along with inflammation in the lung (pink and purple cells represent neutrophil and macrophage influx). The thickened mucus environment generates anaerobic pockets which are colonized by oral anaerobic bacteria (gray bacteria). Anaerobic bacteria “terraform” the mucus environment through breaking down of mucin glycoproteins (indicated by green hexagons) giving rise to pathogen colonization. Over time, P. aeruginosa (red bacteria) becomes the dominant pathogen, adapting to a chronic lifestyle, and persisting despite the use of regular antibiotic therapy. Figure created using BioRender.