scholarly journals Single nucleotide variants in Pseudomonas aeruginosa populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis

2021 ◽  
Author(s):  
Morteza M Saber ◽  
Jannik Donner ◽  
Inès Levade ◽  
Nicole Acosta ◽  
Michael D Perkins ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Genetic Variation ◽  
Lung Function ◽  
Lung Disease ◽  
Disease Severity ◽  
Single Nucleotide Variants ◽  
Lung Function Decline ◽  
Single Nucleotide ◽  
Lung Disease Severity

Complex polymicrobial communities inhabit the lungs of individuals with cystic fibrosis (CF) and contribute to the decline in lung function. However, the severity of lung disease and its progression in CF patients are highly variable and imperfectly predicted by host clinical factors at baseline, CFTR mutations in the host genome, or sputum polymicrobial community variation. The opportunistic pathogen Pseudomonas aeruginosa (Pa) dominates airway infections in the majority of CF adults. Here we hypothesized that genetic variation within Pa populations would be predictive of lung disease severity. To quantify Pa genetic variation within whole CF sputum samples, we used deep amplicon sequencing on a newly developed custom Ion AmpliSeq panel of 209 Pa genes previously associated with the host pathoadaptation and pathogenesis of CF infection. We trained machine learning models using Pa single nucleotide variants (SNVs), clinical and microbiome diversity data to classify lung disease severity at the time of sputum sampling, and to predict future lung function decline over five years in a cohort of 54 adult CF patients with chronic Pa infection. The models using Pa SNVs alone classified baseline lung disease with good sensitivity and specificity, with an area under the receiver operating characteristic curve (AUROC) of 0.87. While the models were less predictive of future lung function decline, they still achieved an AUROC of 0.74. The addition of clinical data to the models, but not microbiome community data, yielded modest improvements (baseline lung function: AUROC=0.92; lung function decline: AUROC=0.79), highlighting the predictive value of the AmpliSeq data. Together, our work provides a proof-of-principle that Pa genetic variation in sputum is strongly associated with baseline lung disease, moderately predicts future lung function decline, and provides insight into the pathobiology of Pa's effect on CF.

scholarly journals SLC6A14 impacts cystic fibrosis lung disease severity via mTOR and epithelial repair modulation

2022 ◽  
Author(s):  
Julia Mercier ◽  
Claire Calmel ◽  
Julie Mésinèle ◽  
Erika Sutanto ◽  
Fatiha Merabtene ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Disease Severity ◽  
Promoter Activity ◽  
Mammalian Target Of Rapamycin ◽  
Luciferase Reporter ◽  
Lung Function Decline ◽  
Bronchial Epithelial ◽  
Epithelial Repair ◽  
Lung Disease Severity

Abstract Cystic fibrosis (CF), due to variants in CFTR gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 promoter activity using a luciferase reporter and the role of SLC6A14 in mammalian target of rapamycin (mTOR) signaling pathway and airway epithelial repair. We confirm that SLC6A14 rs3788766 SNP is associated with lung disease severity in pwCF (p=0.020; n=3,257, pancreatic insufficient, aged 6 to 40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that SLC6A14 genotype might affect lung disease severity of people with cystic fibrosis via mTOR and epithelial repair mechanisms modulation in the lung.

SLC6A14 Modulates Lung Disease Severity in Cystic Fibrosis and Affects mTOR Phosphorylation and Bronchial Epithelial Repair

2021 ◽  
Author(s):  
Julia Mercier ◽  
Claire Calmel ◽  
Julie Mésinèle ◽  
Erika Sutanto ◽  
Fatiha Merabtene ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Disease Severity ◽  
Promoter Activity ◽  
Mtor Signaling ◽  
Bronchial Epithelial ◽  
Epithelial Repair ◽  
Mtor Phosphorylation ◽  
Lung Disease Severity

Abstract Cystic fibrosis (CF), due to variants in CFTR gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 promoter activity and the role of SLC6A14 in mammalian target of rapamycin (mTOR) signaling pathway and airway epithelial repair. We confirm that SLC6A14 SNP rs3788766 is associated with lung disease severity in pwCF (p=0.020; n=3,257, pancreatic insufficient, aged 6 to 40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation and bronchial epithelial repair rates in wound healing assays. In conclusion, SLC6A14 rs3788766 G allele is associated with lower lung function in pwCF. SLC6A14, whose transcriptional promoter activity varies according to rs3788766 genotype, is involved in mTOR signaling and bronchial epithelial repair. This study suggests that SLC6A14 might influence CF lung phenotype via mTOR and epithelial repair mechanisms modulation.

scholarly journals SLC6A14 impacts cystic fibrosis lung disease severity via mTOR and epithelial repair modulation

2021 ◽  
Author(s):  
Julia Mercier ◽  
Claire Calmel ◽  
Julie Mésinèle ◽  
Erika Sutanto ◽  
Fatiha Merabtene ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Disease Severity ◽  
Promoter Activity ◽  
Mammalian Target Of Rapamycin ◽  
Luciferase Reporter ◽  
Lung Function Decline ◽  
Bronchial Epithelial ◽  
Epithelial Repair ◽  
Lung Disease Severity

Abstract Cystic fibrosis (CF), due to variants in CFTR gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 promoter activity using a luciferase reporter and the role of SLC6A14 in mammalian target of rapamycin (mTOR) signaling pathway and airway epithelial repair. We confirm that SLC6A14 SNP rs3788766 is associated with lung disease severity in pwCF (p=0.020; n=3,257, pancreatic insufficient, aged 6 to 40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that SLC6A14 genotype might affect lung disease severity of people with cystic fibrosis via mTOR and epithelial repair mechanisms modulation in the lung.

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

scholarly journals Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients

2012 ◽  
Vol 11 (1) ◽  
pp. 63-67 ◽  
Author(s):  
Harriet Corvol ◽  
Julie Beucher ◽  
Pierre-Yves Boëlle ◽  
Pierre-François Busson ◽  
Céline Muselet-Charlier ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Disease Severity ◽  
Ancestral Haplotype ◽  
Lung Disease Severity

scholarly journals An 8 week open-label interventional multicenter study to evaluate the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥8 years of age, chronically infected with Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Sivagurunathan Sutharsan ◽  
Susanne Naehrig ◽  
Uwe Mellies ◽  
Christian Sieder ◽  
joerg Zeigler
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Lung Disease ◽  
Small Airways ◽  
Open Label ◽  
Lung Clearance ◽  
Efficacy Trials ◽  
Inhaled Antibiotics ◽  
Lung Clearance Index

Abstract Background Forced expiratory volume in 1 second (FEV 1 ) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV 1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to evaluate the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF. Methods This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV 1 , LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment. Results All patients (n=17) showed elevated LCI of >11 despite 3 patients having normal FEV 1 (>90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV 1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV 1 increased by 0.52%, and P. aeruginosa reduced by 30481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity. Conclusions Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities. Trial registration : The study is registered with ClinicalTrials.gov, identifier: NCT02248922

scholarly journals Sputum microbiota is predictive of long-term clinical outcomes in young adults with cystic fibrosis

Thorax ◽  
2018 ◽  
Vol 73 (11) ◽  
pp. 1016-1025 ◽  
Author(s):  
Nicole Acosta ◽  
Alya Heirali ◽  
Ranjani Somayaji ◽  
Michael G Surette ◽  
Matthew L Workentine ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Microbial Communities ◽  
Multivariable Analysis ◽  
Alpha Diversity ◽  
Illumina Miseq ◽  
Disease Stage ◽  
Sample Collection ◽  
Lung Function Decline

BackgroundComplex polymicrobial communities infect cystic fibrosis (CF) lower airways. Generally, communities with low diversity, dominated by classical CF pathogens, associate with worsened patient status at sample collection. However, it is not known if the microbiome can predict future outcomes. We sought to determine if the microbiome could be adapted as a biomarker for patient prognostication.MethodsWe retrospectively assessed prospectively collected sputum from a cohort of 104 individuals aged 18–22 to determine factors associated with progression to early end-stage lung disease (eESLD; death/transplantation <25 years) and rapid pulmonary function decline (>−3%/year FEV1 over the ensuing 5 years). Illumina MiSeq paired-end sequencing of the V3-V4 region of the 16S rRNA was used to define the airway microbiome.ResultsBased on the primary outcome analysed, 17 individuals (16%) subsequently progressed to eESLD. They were more likely to have sputum with low alpha diversity, dominated by specific pathogens including Pseudomonas. Communities with abundant Streptococcus were observed to be protective. Microbial communities clustered together by baseline lung disease stage and subsequent progression to eESLD. Multivariable analysis identified baseline lung function and alpha diversity as independent predictors of eESLD. For the secondary outcomes, 58 and 47 patients were classified as rapid progressors based on absolute and relative definitions of lung function decline, respectively. Patients with low alpha diversity were similarly more likely to be classified as experiencing rapid lung function decline over the ensuing 5 years when adjusted for baseline lung function.ConclusionsWe observed that the diversity of microbial communities in CF airways is predictive of progression to eESLD and disproportionate lung function decline and may therefore represent a novel biomarker.

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