Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction Research Articles

Celiac Disease in Patients With Cystic Fibrosis on Ivacaftor: A Case Series.

Cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators have revolutionized care for individuals with cystic fibrosis (CF) with positive effects on the gastrointestinal (GI) tract. There is emerging evidence linking CFTR dysfunction to celiac disease (CD). We present 3 cases of patients with CF, genotype F508del/G551D, treated with CFTR modulator, ivacaftor, and diagnosed with CD. These patients tested for CD because they had persistent GI symptoms that had partially improved with ivacaftor. This case series highlights the importance of a better understanding of how CFTR modulators impact the GI tract, their possible link to CD, and the importance of considering CD when evaluating GI symptoms in individuals with CF.

Platelets: inflammatory effector cells in the conflagration of cystic fibrosis lung disease.

Cystic fibrosis (CF) is a multisystem disorder, but progressive inflammatory lung disease causes the greatest burden of morbidity and death. Recent translational and mechanistic studies of samples from patients, and observations in animal models, indicate that platelets may drive lung injury and contribute to dysregulated host defense in CF lung disease. In this issue of the JCI, Ortiz-Muñoz and Yu et al. explored the role that the cystic fibrosis transmembrane conductance regulator (CFTR) plays in platelet-related inflammation. The authors used mouse and human model systems to show that CFTR dysfunction in platelets increased calcium entry though the transient receptor potential cation channel 6 (TRPC6), causing hyperactivation and consequent experimental lung inflammation. The study persuasively suggests that platelets are critical thromboinflammatory effector cells in CF lung disease. In the context of platelet-related organ injury seen in a variety of other diseases and syndromes, platelets may also contribute to nonpulmonary manifestations and comorbidities of CF.

Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.

Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets and TRPC6 are what we believe to be novel therapeutic targets in the treatment of CF lung disease.

Re-imagining cystic fibrosis care: next generation thinking.

Cystic fibrosis (CF) is a common multi-system genetically inherited condition, predominately found in individuals of Caucasian decent. Since the identification of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect: the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality-of-life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all; whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised individualised therapy would ideally be the mainstay of CF care.

The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis.

The effects of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on lung function, pulmonary exacerbations, and quality of life have been well documented. However, CF is a multiorgan disease, and therefore an evidence base is emerging on the systemic effects of CFTR modulators beyond the pulmonary system. This is of great clinical importance, as many of these studies provide proof of concept that CFTR modulators might be used one day to prevent or treat extrapulmonary manifestations stemming from CFTR dysfunction. In this concise review of the literature, we summarize the results of key publications that have evaluated the effects of CFTR modulators on weight and growth, pancreatic function, the gastrointestinal and hepatobiliary systems, sinus disease, bone disease, exercise tolerance, fertility, mental health, and immunity. Although many of these studies have reported beneficial extrapulmonary effects related to the use of ivacaftor (IVA) in patients with CF with at least one gating mutation, most of the evidence is low or very low quality, given the limited number of patients evaluated and the lack of control groups. Based on an even smaller number of studies evaluating the extrapulmonary effects of lumacaftor-IVA, the benefits are less clear. Although limited, these studies may provide the basis for future clinical trials to evaluate CFTR modulators on the extrapulmonary manifestations of CF.

Conformational Dynamics of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Revealed by Molecular Simulations

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that supports functions of secretory organs. Dysfunctional CFTR in humans causes Cystic Fibrosis (CF), a lethal disease that results in the failure of lungs and various secretory glands. Phosphorylation and ATP-binding were shown to lead to the opening of the gate in CFTR; however, several recent near-atomistic cryo-EM structures of phosphorylated, ATP-bound CFTR remain in an apparently closed state, as suggested by the presence of a constriction at the extracellular end of the channel. We hypothesize that the cryo-EM structure of CFTR may relax to a functionally open state when placed in a lipid bilayer. To test this hypothesis, we performed repeated microsecond-long atomistic molecular dynamics (MD) simulations on the ATP-bound structures of CFTR in explicit pure POPC and POPS bilayers. In 2 out of 40 MD time trajectories, structural relaxation in the transmembrane domains of the channel leads to putatively open or pre-open states characterized by the presence of continuous pathways of hydrogen-bonded water molecules. Specifically, local conformational transitions involving changes in helical bend correlate with the formation of continuous water pathways. Potential of mean force calculations for chloride translocation through the channel are currently underway to validate the putatively open or pre-open configurations of CFTR obtained from simulations.

Mycobacterium abscessus, an Emerging and Worrisome Pathogen among Cystic Fibrosis Patients.

Nontuberculous mycobacteria (NTM) have recently emerged as important pathogens among cystic fibrosis (CF) patients worldwide. Mycobacterium abscessus is becoming the most worrisome NTM in this cohort of patients and recent findings clarified why this pathogen is so prone to this disease. M. abscessus drug therapy takes up to 2 years and its failure causes an accelerated lung function decline. The M. abscessus colonization of lung alveoli begins with smooth strains producing glycopeptidolipids and biofilm, whilst in the invasive infection, “rough” mutants are responsible for the production of trehalose dimycolate, and consequently, cording formation. Human-to-human M. abscessus transmission was demonstrated among geographically separated CF patients by whole-genome sequencing of clinical isolates worldwide. Using a M. abscessus infected CF zebrafish model, it was demonstrated that CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction seems to have a specific role in the immune control of M. abscessus infections only. This pathogen is also intrinsically resistant to many drugs, thanks to its physiology and to the acquisition of new mechanisms of drug resistance. Few new compounds or drug formulations active against M. abscessus are present in preclinical and clinical development, but recently alternative strategies have been investigated, such as phage therapy and the use of β-lactamase inhibitors.

Anti-inflammatories and mucociliary clearance therapies in the age of CFTR modulators.

Cystic fibrosis (CF) is a genetic and life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This multi-system disease is characterized by progressive lung disease and pancreatic insufficiency amongst other manifestations. CFTR primarily functions as a chloride channel that transports ions across the apical membrane of epithelial cells but has other functions, including bicarbonate secretion and inhibition of sodium transport. Defective CFTR disrupts these functions, causing viscous and dehydrated mucus to accumulate, compromising the airway lumen and contributing to obstructive pulmonary disease. The combination of CFTR dysfunction, mucus obstruction, and infection drive an exaggerated and dysfunctional inflammatory response, which contributes to irreversible airway destruction and fibrosis. CFTR modulators, an exciting new class of drugs, increase the expression and/or function of CFTR variant protein and improve multiple clinical endpoints, such as lung function, pulmonary exacerbation rates, and nutritional status. However, these genotype-specific drugs are not universally available, the clinical response is variable, and lung function still declines over time when bronchiectasis is established. Consequently, even in the age of CFTR modulators, we must target other important aspects of the CF airway disease, such as inflammation and mucociliary clearance. This review highlights the mechanisms of inflammation and mucus accumulation in the CF lung and discusses anti-inflammatory and mucociliary clearance agents that are currently in development focusing on compounds for which clinical trial data have recently become available.

Treating the Airway Consequences of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction

In cystic fibrosis (CF), absent or dysfunctional CF transmembrane conductance regulator (CFTR) on the surface of airway epithelial cells causes abnormal mucociliary clearance, leading to chronic endobronchial infection and inflammation, in turn resulting in life-shortening progressive obstructive lung disease and structural airway damage. Fortunately, CF-specific therapies have been developed that improve lung function and reduce pulmonary exacerbations, contributing significantly to improved survival over the past 4 decades. Therapies not originally developed for CF, such as bronchodilators and corticosteroids, are also widely used by people living with CF. Therapies to be reviewed in this article include mucolytics, airway surface liquid hydrators, anti-inflammatory medications, bronchodilators, inhaled and oral antibiotics, and airway clearance techniques. Determining which therapies to utilize can be challenging, as there is variable evidence for each treatment, differing national guidelines, few head-to-head studies, potential for drug-drug interactions, and synergistic toxicities, as well as issues with burden of care. In this review, we summarize the mechanism of action and available evidence, and compare national guidelines for each major medication used to treat the airway consequences of CFTR dysfunction.

Immunoreactive trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis

BackgroundNewborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that immunoreactive trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF.MethodsIn this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016.ResultsNinety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8–206.2) vs. 75.0 (61.0–105.9); P < 0.0001). Infants with CRMS/CFSPID→CF (n = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID (n = 83) (median (interquartile range): 108.9 (72.3–126.8) vs. 73.7(60.0–96.0); P = 0.02).ConclusionsAmongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.

Devil in the detail of newborn screening for cystic fibrosis

The recognition that the sweat chloride concentration was elevated in people with cystic fibrosis (CF) was fundamental to its diagnosis and treatment.1 A sweat chloride >60 mmol/L was diagnostic of...

ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis.

Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation.

A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia.

Cystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, these results were used to inform a quantitative systems pharmacology model of airway epithelium describing electrically and chemically driven transcellular ionic transport, contributions of both convective and diffusive paracellular solute transport, and osmotically driven transepithelial water dynamics. Model predictions showed CF cultures, relative to non-CF ones, have increased apical and basolateral water permeabilities, and increase paracellular permeability and transepithelial chemical driving force for a radiolabeled tracer used to track small molecule absorption. These results provide a computational platform to better understand and probe the mechanisms behind the liquid hyperabsorption and small molecule retention profiles observed in the CF airway.

Vaporized E-Cigarette Liquids Induce Ion Transport Dysfunction in Airway Epithelia.

Cigarette smoking is associated with chronic obstructive pulmonary disease and chronic bronchitis. Acquired ion transport abnormalities, including cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, caused by cigarette smoking have been proposed as potential mechanisms for mucus obstruction in chronic bronchitis. Although e-cigarette use is popular and perceived to be safe, whether it harms the airways via mechanisms altering ion transport remains unclear. In the present study, we sought to determine if e-cigarette vapor, like cigarette smoke, has the potential to induce acquired CFTR dysfunction, and to what degree. Electrophysiological methods demonstrated reduced chloride transport caused by vaporized e-cigarette liquid or vegetable glycerin at various exposures (30 min, 57.2% and 14.4% respectively, vs. control; P < 0.0001), but not by unvaporized liquid (60 min, 17.6% vs. untreated), indicating that thermal degradation of these products is required to induce the observed defects. We also observed reduced ATP-dependent responses (-10.8 ± 3.0 vs. -18.8 ± 5.1 μA/cm2 control) and epithelial sodium channel activity (95.8% reduction) in primary human bronchial epithelial cells after 5 minutes, suggesting that exposures dramatically inhibit epithelial ion transport beyond CFTR, even without diminished transepithelial resistance or cytotoxicity. Vaporizing e-cigarette liquid produced reactive aldehydes, including acrolein (shown to induce acquired CFTR dysfunction), as quantified by mass spectrometry, demonstrating that respiratory toxicants in cigarette smoke can also be found in e-cigarette vapor (30 min air, 224.5 ± 15.99; unvaporized liquid, 284.8 ± 35.03; vapor, 54,468 ± 3,908 ng/ml; P < 0.0001). E-cigarettes can induce ion channel dysfunction in airway epithelial cells, partly through acrolein production. These findings indicate a heretofore unknown toxicity of e-cigarette use known to be associated with chronic bronchitis onset and progression, as well as with chronic obstructive pulmonary disease severity.

Image-based β-adrenergic sweat rate assay captures minimal cystic fibrosis transmembrane conductance regulator function.

Background:There is a need to prognosticate the severity of cystic fibrosis (CF) detected by newborn screening (NBS) by early assessment of CF Transmembrane Conductance Regulator protein function (CFTR). We introduce novel instrumentation and protocol for evaluating CFTR activity as reflected by β-adrenergically stimulated sweat secretion.Methods:A pixilated Image-Sensor detects sweat rates. Compounds necessary for maximum sweat gland stimulation are applied by Iontophoresis, replacing intradermal injections. Results are compared to a validated β-adrenergic assay that measures sweat secretion by evaporation (Evaporimetry).Results:Ten healthy controls (HC), 6 Heterozygous (Carriers), 5 with cystic fibrosis screen positive, inconclusive diagnosis (CFSPID), and 12 cystic fibrosis (CF) individuals completed testing. All individuals with minimal and residual function CFTR mutations had low ratios of β-adrenergically stimulated sweat rate to cholinergically stimulated sweat rate (β/chol) as measured by either assay.Conclusions:β adrenergic assays quantitate CFTR dysfunction in the secretory pathway of sweat glands in CF and CRMS/CFSPID populations. This novel Image-Sensor and Iontophoresis protocol detect CFTR function with minimal and residual function and is a feasible test for young children because it is insensible to movement and it decreases the number of injections. It may also assist to distinguish between CF and CRMS/CFSPID diagnosis.

CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

Transcriptional consequences of impaired immune cell responses induced by cystic fibrosis plasma characterized via dual RNA sequencing

BackgroundIn cystic fibrosis (CF), impaired immune cell responses, driven by the dysfunctional CF transmembrane conductance regulator (CFTR) gene, may determine the disease severity but clinical heterogeneity remains a major therapeutic challenge. The characterization of molecular mechanisms underlying impaired immune responses in CF may reveal novel targets with therapeutic potential. Therefore, we utilized simultaneous RNA sequencing targeted at identifying differentially expressed genes, transcripts, and miRNAs that characterize impaired immune responses triggered by CF and its phenotypes.MethodsPeripheral blood mononuclear cells (PBMCs) extracted from a healthy donor were stimulated with plasma from CF patients (n = 9) and healthy controls (n = 3). The PBMCs were cultured (1 × 105 cells/well) for 9 h at 37 ° C in 5% CO2. After culture, total RNA was extracted from each sample and used for simultaneous total RNA and miRNA sequencing.ResultsAnalysis of expression signatures from peripheral blood mononuclear cells induced by plasma of CF patients and healthy controls identified 151 genes, 154 individual transcripts, and 41 miRNAs differentially expressed in CF compared to HC while the expression signatures of 285 genes, 241 individual transcripts, and seven miRNAs differed due to CF phenotypes. Top immune pathways influenced by CF included agranulocyte adhesion, diapedesis signaling, and IL17 signaling, while those influenced by CF phenotypes included natural killer cell signaling and PI3K signaling in B lymphocytes. Upstream regulator analysis indicated dysregulation of CCL5, NF-κB and IL1A due to CF while dysregulation of TREM1 and TP53 regulators were associated with CF phenotype. Five miRNAs showed inverse expression patterns with three target genes relevant in CF-associated impaired immune pathways while two miRNAs showed inverse expression patterns with two target genes relevant to a dysregulated immune pathway associated with CF phenotypes.ConclusionsOur results indicate that miRNAs and individual transcript variants are relevant molecular targets contributing to impaired immune cell responses in CF.

CFTR interacts with Hsp90 and regulates the phosphorylation of AKT and ERK1/2 in colorectal cancer cells.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF cells and tissues exhibit various mitochondrial abnormalities. However, the underlying molecular mechanisms remain elusive. Here, we examined the mechanisms through which CFTR regulates Bcl‐2 family proteins, which in turn regulate permeabilization of the mitochondrial outer membrane. Notably, inhibition of CFTR activated Bax and Bad, but inhibited Bcl‐2. Moreover, degradation of phosphorylated extracellular signal‐regulated kinase 1/2 (ERK1/2) and AKT increased significantly in CFTR‐knockdown cells. Dysfunction of CFTR decreased heat‐shock protein 90 (Hsp90) mRNA levels, and CFTR was found to interact with Hsp90. Inhibition of Hsp90 by SNX‐2112 induced the degradation of phosphorylated AKT and ERK1/2 in Caco2 and HRT18 cells. These findings may help provide insights into the physiological role of CFTR in CF‐related diseases.

Mutation-specific therapies and drug repositioning in cystic fibrosis.

Cystic fibrosis (CF) is an inherited, prematurely lethal rare disease affecting more than 85,000 people worldwide. CF is caused by more than 2000 loss-of-function mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). This review summarizes recent advances in the etiological therapies of CF that aim at repairing the functional defect of CFTR by means of CFTR modulators. We will discuss the state of art of the mutation-specific treatments that are designed to target different steps of the CFTR biogenesis perturbed by mutations in CFTR gene. Moreover, we will discuss how drug repositioning, namely the use of drugs already approved for the treatment of other human diseases, may be repurposed in CF patients to circumvent CFTR dysfunction. Finally, we highlight how the combined use of two or more compounds acting on different disease mechanisms is required to achieve clinical benefit in CF population.

CFTR Protects against Mycobacterium abscessus Infection by Fine-Tuning Host Oxidative Defenses

Infection by rapidly growing Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF), a genetic disease caused by a defective CF transmembrane conductance regulator (CFTR). However, the potential link between a dysfunctional CFTR and vulnerability to M.abscessus infection remains unknown. Herein, we exploit a CFTR-depleted zebrafish model, recapitulating CF immuno-pathogenesis, to study the contribution of CFTR in innate immunity against M.abscessus infection. Loss of CFTR increases susceptibility to infection through impaired NADPH oxidase-dependent restriction of intracellular growth and reduced neutrophil chemotaxis, which together compromise granuloma formation and integrity. As a consequence, extracellular multiplication of M.abscessus expands rapidly, inducing abscess formation and causing lethal infections. Because these phenotypes are not observed with other mycobacteria, our findings highlight the crucial and specific role of CFTR in the immune control of M.abscessus by mounting effective oxidative responses.