Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

Abstract

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathology of pwCF.

Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors

“…Cystic fibrosis (CF) is a rare and fatal disease caused by a defective mutated cystic fibrosis transmembrane regulator (CFTR) protein, an anion channel that regulates fluid secretion in glandular organs such as the lungs, pancreas, and reproductive organs [ 170 ]. In CF patients, P. aeruginosa is a major cause of morbidity and mortality and promotes rapid decline in respiratory function [ 210 ]. The involvement of P. aeruginosa in the natural history of CF and its ability to produce T2R38 ligands led scientists to investigate the relationship between susceptibility to this bacterium and TASR38 genotype in CF patients.…”

“…Altered CFTR function may therefore be responsible for a decreased innate immune response in CF patients, independent of their TASR38 genotype, contributing to their high susceptibility to P. aeruginosa and reducing the influence of TAS2R38 on CF-related infections. With current CF treatments using CFTR modulators to restore the ion channel function in patients [ 210 , 215 ], we may begin to observe a greater impact of TASR38 genetics on the susceptibility of CF patients to P. aeruginosa infections.…”

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways

“…A strategy to address this question is to explore which type of CFTR function, once impaired, causes recurrent airway bacterial infection, a key step that elicits excess inflammatory responses and consequent tissue damage in the CF lung ( Cabrini et al, 2020 ; Ribeiro et al, 2023 ). The physicochemical properties and movement of mucus is another key factor altered upon CF epithelia ( Matsui et al, 1998 ; Hoegger et al, 2014 ; Esther et al, 2019 ; Keith et al, 2022 ).…”

“…Moreover, bacterial killing on the apical side of epithelia is attenuated in CF ( Smith et al, 1996 ; Pezzulo et al, 2012 ). Therefore, both mucus accumulation and weakened bactericidal activity in ASL may prevent CF airway epithelia from removing airborne bacteria and lead to bacterial colonization ( Stoltz et al, 2015 ; Ribeiro et al, 2023 ).…”

Immune Response in Cystic Fibrosis: Interplay between the Host and Microbes

“…However, the impact of these therapies on cellular immune response and infection remains poorly understood. With the advent of these new disease-modifying treatments for those who have access to them, there is great interest in understanding their impact on the microbiome's evolution and the mechanisms of microbial infection in CF [5], and a deeper exploration of the host cellular immune response and the microbial mechanisms involved in evading the host or treatment response is necessary to develop new therapeutic strategies.…”