The Impact of Highly Effective Modulator Therapy on Cystic Fibrosis Microbiology and Inflammation

Abstract

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) corrects the underlying molecular defect causing CF disease. HEMT decreases symptom burden and improves clinical metrics and quality of life for most people with CF (PwCF) and eligible cftr mutations. Improvements in measures of pulmonary health suggest that restoration of function of defective CFTR anion channels by HEMT not only enhances airway mucociliary clearance, but also reduces chronic pulmonary infection and inflammation. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of infection and inflammation in the CF airway, and what questions remain unanswered.

Keywords: Cystic fibrosis; Cystic fibrosis transmembrane regulator; Highly effective cystic fibrosis transmembrane conductance regulator modulator therapy (HEMT); Infection; Inflammation; Modulator.

Fig. 1.

Pulmonary damage in CF is associated with abnormal anion secretion, inflammation, and infection. (A) In contrast with healthy individuals, the CF lung exhibits many physiologic dysregulations, including abnormal secretion of ions and impaired mucociliary clearance, nonresolving inflammation, airway infection, and progressive bronchiectasis. These processes amplify each other and contribute to the long-term respiratory morbidity. (B) Impact of CFTR dysfunction (eg, F508del) on the many networks that promote airway injury. Lack of CFTR function in epithelial cells compromises airway anion balance favoring accumulation of an abnormal mucus layer that traps inhaled or aspirated bacteria. Certain CF pathogens with specific genetic and metabolic properties outcompete other members of the airway microbiome in the CF lung, which is detrimental for lung homeostasis. CFTR function deficiency in both epithelial and myeloid cells stimulates release of inflammatory mediators, which contribute to airway damage, release of damage-associated molecular patterns (DAMPs), and infection. These processes culminate in progressive pulmonary function decline and clinical deterioration.

Fig. 2.

CF myeloid cells exhibit proinflammatory metabolic dysregulation. (A) In healthy myeloid cells, WT CFTR interacts with many proteins at the cell membrane, including PTEN. PTEN not only restricts ROS generation, but also promotes OXPHOS and energy synthesis by mitochondria. Glycolysis is low, limiting the production of inflammatory mediators that rely on carbohydrate breakdown. (B) Myeloid cells harboring type II CFTR mutations accumulate CFTR in the endoplasmic reticulum (ER). This produces ER stress, promoting glycolysis and inflammatory signaling. Lack of surface-attached CFTR also compromises the ability of CF cells to regulate OXPHOS, prompting ROS release. One factor contributing to this OXPHOS dysregulation is reduced interaction of CFTR with PTEN. CFTR-PTEN complex dysfunction favors secretion of succinate and itaconate, which stimulate synthesis of extracellular polysaccharides (EPSs) and biofilm by S aureus and. P aeruginosa. (C) Myeloid cells harboring type III CFTR mutations secrete potassium, which activates inflammatory pathways that rely on glycolysis, such as the inflammasome. As a consequence of increased glycolysis, mitochondrial OXPHOS is jeopardized, contributing to ROS release and inflammatory damage.