Mutual Effects of Single and Combined CFTR Modulators and Bacterial Infection in Cystic Fibrosis

Cigana, Cristina; Giannella, R.; Colavolpe, Alice; Alcalá-Franco, Beatriz; Mancini, Giulia; Francesca, Colombi; Bigogno, Chiara; Bastrup, Ulla; Bertoni, Giovanni; Bragonzi, Alessandra

doi:10.1128/spectrum.04083-22

Cited by 12 publications

(4 citation statements)

References 47 publications

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“…A recent study compared the ability of HEMTs VX-770 versus ETI to synergize with antibiotics, and found that ETI treatment did not enhance the activity of most antibiotics against P. aeruginosa clinical isolates, with the exception of polymyxin B. The additive effect of ETI with polymyxin B was also seen in bacterial isolates treated with VX-770 alone, indicating that the other correctors in ETI (VX-445 and VX-661) do not contribute to the antibiotic-enhancing activity of VX-770 [73].…”

Section: Discussionmentioning

confidence: 99%

A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection

Cholon,

Greenwald,

Higgs

et al. 2023

Cells

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People with cystic fibrosis (pwCF) suffer from chronic and recurring bacterial lung infections that begin very early in life and contribute to progressive lung failure. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes an ion channel important for maintaining the proper hydration of pulmonary surfaces. When CFTR function is ablated or impaired, airways develop thickened, adherent mucus that contributes to a vicious cycle of infection and inflammation. Therapeutics for pwCF, called CFTR modulators, target the CFTR defect directly, restoring airway surface hydration and mucociliary clearance. However, even with CFTR modulator therapy, bacterial infections persist. To develop a relevant model of diseased airway epithelium, we established a primary human airway epithelium culture system with persistent Pseudomonas aeruginosa infection. We used this model to examine the effects of CFTR modulators on CFTR maturation, CFTR function, and bacterial persistence. We found that the presence of P. aeruginosa increased CFTR mRNA, protein, and function. We also found that CFTR modulators caused a decrease in P. aeruginosa burden. These results demonstrate the importance of including live bacteria to accurately model the CF lung, and that understanding the effects of infection on CFTR rescue by CFTR modulators is critical to evaluating and optimizing drug therapies for all pwCF.

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Section: Discussionmentioning

confidence: 99%

A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection

Cholon,

Greenwald,

Higgs

et al. 2023

Cells

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“…A recent study that investigated the ability of HEMT and antibiotics to synergize found minimal effects. It was found that ETI treatment did not impact the efficacy of most antibiotics against P. aeruginosa clinical isolates, with the exception of polymyxin B. Interestingly, the additive effect of ETI with polymyxin B was also seen in ivacaftor alone-treated isolates, indicating that elexacaftor or tezacaftor are devoid of additional synergistic abilities for HEMT [212]. Further, the effect of HEMT on the polymyxin B efficacy against P. aeruginosa may not be related to any direct effect on the bacteria, but may be a result of the mucus clearance and reduced mucus content in the airways, as the polymyxins are known to be inhibited by mucins due to the charge-charge interactions.…”

Section: Effects Of Cftr Modulators On Airway Mucus Inflammation and ...mentioning

confidence: 98%

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

Ribeiro

Higgs

Muhlebach

et al. 2023

IJMS

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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.

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“…Chronic P. aeruginosa infections are managed using long-term suppressive therapy with inhaled antibiotics,14 with clinical guidelines providing specific recommendations 15 16. In recent years, studies have reported that CFTRm may reduce P. aeruginosa bacterial load32 33; however, the mechanisms behind this apparent effect are not clear 35 68–70. In addition, there have been suggestions of a molecular synergy between inhaled antibiotics and CFTRm,33 68 but this evidence is inconclusive, with one study reporting that while the bacterial density of P. aeruginosa decreased in highly responsive pwCF receiving CFTRm alongside intensive antibiotics, very few individuals cleared their infection 33.…”

Section: Inhaled Antibiotics Alongside Cftrm Therapymentioning

confidence: 99%

“…In recent years, studies have reported that CFTRm may reduce P. aeruginosa bacterial load32 33; however, the mechanisms behind this apparent effect are not clear 35 68–70. In addition, there have been suggestions of a molecular synergy between inhaled antibiotics and CFTRm,33 68 but this evidence is inconclusive, with one study reporting that while the bacterial density of P. aeruginosa decreased in highly responsive pwCF receiving CFTRm alongside intensive antibiotics, very few individuals cleared their infection 33. Those with persistent infections retained their pretreatment strains during 2.5 years of follow-up 33.…”

Section: Inhaled Antibiotics Alongside Cftrm Therapymentioning

confidence: 99%

Considerations for the use of inhaled antibiotics forPseudomonas aeruginosain people with cystic fibrosis receiving CFTR modulator therapy

Burgel,

Ballmann,

Drevinek

et al. 2024

BMJ Open Resp Res

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The major cause of mortality in people with cystic fibrosis (pwCF) is progressive lung disease characterised by acute and chronic infections, the accumulation of mucus, airway inflammation, structural damage and pulmonary exacerbations. The prevalence ofPseudomonas aeruginosarises rapidly in the teenage years, and this organism is the most common cause of chronic lung infection in adults with cystic fibrosis (CF). It is associated with an accelerated decline in lung function and premature death. NewP. aeruginosainfections are treated with antibiotics to eradicate the organism, while chronic infections require long-term inhaled antibiotic therapy. The prevalence ofP. aeruginosainfections has decreased in CF registries since the introduction of CF transmembrane conductance regulator modulators (CFTRm), but clinical observations suggest that chronicP. aeruginosainfections usually persist in patients receiving CFTRm. This indicates that pwCF may still need inhaled antibiotics in the CFTRm era to maintain long-term control ofP. aeruginosainfections. Here, we provide an overview of the changing perceptions ofP. aeruginosainfection management, including considerations on detection and treatment, the therapy burden associated with inhaled antibiotics and the potential effects of CFTRm on the lung microbiome. We conclude that updated guidance is required on the diagnosis and management ofP. aeruginosainfection. In particular, we highlight a need for prospective studies to evaluate the consequences of stopping inhaled antibiotic therapy in pwCF who have chronicP. aeruginosainfection and are receiving CFTRm. This will help inform new guidelines on the use of antibiotics alongside CFTRm.

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Mutual Effects of Single and Combined CFTR Modulators and Bacterial Infection in Cystic Fibrosis

Abstract: CFTR modulators have been developed to correct and/or enhance CFTR activity in patients with specific cystic fibrosis (CF) genotypes. However, it is of great importance to identify potential off-targets of these novel therapies to understand how they affect lung physiology in CF.

Cited by 12 publications

References 47 publications

A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection

A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection

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

Considerations for the use of inhaled antibiotics forPseudomonas aeruginosain people with cystic fibrosis receiving CFTR modulator therapy

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