LumIvaBiota
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB53549 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR9866510_1.fastq.gz | Fastqsanger.gz | |||
| ERR9866510_2.fastq.gz | Fastqsanger.gz | |||
| ERR9866520_1.fastq.gz | Fastqsanger.gz | |||
| ERR9866520_2.fastq.gz | Fastqsanger.gz | |||
| ERR9866530_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 404 |
Similar Datasets
Project description:Cystic fibrosis (CF) remains a life-shortening disease without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are now in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR mutation p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response. Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation with clinical variables was performed by stratification via clinical responses. We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls. In addition, 36 genes were differentially expressed when comparing pre-drug to post-drug profiles within CF patients. Transcriptomics revealed novel pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor. Overall changes in gene expression post-lumacaftor/ivacaftor were modest compared to pre-drug CF profiles.
2019-01-03 | GSE124548 | GEO
Project description:Background: CFTR modulators will decrease some etiologies of inflammation in the CF airway; however, current data indicate that non-resolving airway infection and inflammation will persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish CF airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation require a better understanding of the cellular contributions to chronic CF airway disease, and how cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, and represent intriguing targets for focused therapies to dampen CF airway inflammation. Material and Methods: In order to characterize the inflammatory phenotype of CF blood monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq). Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA. Results: RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional pathways were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including transcriptional modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine. These results demonstrate that ivacaftor causes acute changes in blood monocytes and plasma chemokines, and suggest that increased monocyte inflammatory signals and potentially improved trafficking to the lung contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of isolated blood monocytes in CF subjects.
2020-07-31 | GSE148076 | GEO
Project description:Cystic fibrosis (CF) is an inherited, multi-system disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a ubiquitous ion channel important for epithelial hydration. A direct consequence of this dysfunction is impaired mucociliary clearance, chronic airway infection and a persistent neutrophilic inflammatory response that results in progressive loss of lung function, development of respiratory failure and premature death. Partial restoration of CFTR function is now possible for most CF patients through mutation specific CFTR modulators. Ivacaftor monotherapy produces significant clinical improvement in CF patients with the G511D mutation. Dual therapy, combining ivacaftor with lumacaftor or tezacaftor, results in modest clinical improvements in patients homozygous for F508del. More recently, triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic improvements in lung function and quality of life in patients homozygous and heterozygous for F508del. Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms by interrogating the proteome, an entire set of proteins within biological samples. It has confirmed the central role of neutrophilic immune dysregulation in CF and non-CF bronchiectasis, particularly involving the release of antimicrobial proteins and neutrophil-extracellular traps (NETs), and through impaired anti-inflammatory mechanisms. These processes produce distinct molecular signatures within the sputum proteome that become increasingly abnormal with chronic airway infection and progressive lung disease severity. In CF patients, airway and systemic inflammatory cytokines potentially related to these signatures reduce with the various forms of CFTR modulation. To date, no studies of ETI therapy in CF lung disease have assessed large-scale change in protein expression using untargeted proteomics. We hypothesised that ETI therapy would shift the sputum proteome toward health, potentially normalising airway biology in people with CF. The objectives of this study were to investigate changes in the CF sputum proteome with the introduction of ETI, correlate these with changes in clinical markers of disease severity, and make comparisons with the sputum proteome in healthy controls and in repeat samples from CF patients not suitable for ETI therapy. We also explored which molecular pathways associated with CF lung disease did not change with ETI.
2023-11-14 | PXD041950 | Pride
Project description:Transcriptomic Responses to Lumacaftor/Ivacaftor Therapy in Cystic Fibrosis
| PRJNA512474 | ENA
Project description:Rationale: We recently demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves lung ventilation and airway mucus plugging determined by multiple-breath washout and magnetic resonance imaging in CF patients with at least one F508del allele. However, effects of ELX/TEZ/IVA on viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. Objectives: To examine the effects of ELX/TEZ/IVA on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older. Methods: In this prospective observational study, we determined sputum rheology, microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ELX/TEZ/IVA. Measurements and Main Results: CF patients with at least one F508del allele and healthy controls were enrolled in this study. ELX/TEZ/IVA improved the elastic and viscous modulus of CF sputum. Further, ELX/TEZ/IVA improved the microbiome α-diversity and decreased the relative abundance of Pseudomonas aeruginosa (P<0.05) in CF sputum. ELX/TEZ/IVA also reduced IL-8 and free NE activity, and shifted the CF sputum proteome towards healthy. Conclusions: Our data demonstrate that ELX/TEZ/IVA improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele, however, without reaching levels close to healthy.
2023-06-22 | PXD041844 | Pride
Project description:Background: Respiratory viruses including rhinovirus can cause pulmonary exacerbations in cystic fibrosis (CF). Aberrant responses by the CF airway epithelium during rhinovirus infection, particularly interferon production, may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with Ivacaftor or ivacaftor/lumacaftor (Orkambi) would improve control of rhinovirus infection. Methods: Nineteen CF epithelial cultures (CFTR Class 2: 10 homozygous for p.Phe508del, CFTR Class 3: 9 p.Phe508del/p.Gly551Asp) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 hours. Culture RNA and supernatants were harvested to assess gene and protein expression respectively. Results: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated; all infected cultures (+/- treatment) were associated with the same top three over-represented biological pathways associated with interferon signalling, and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3, and only 68 genes for Class 2, related to cell metabolic pathways. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection. Conclusions: Though long term clinical data is not yet available, results presented here suggest CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection.
2020-09-01 | GSE139078 | GEO
Project description:Rationale: Ivacaftor is a recently FDA-approved drug for the treatment of cystic fibrosis (CF) patients with at least one copy of the G511D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The transcriptomic effect of Ivacaftor in CF patients remains unclear. Objectives: We aim to examine if and how the transcriptome of patients is influenced by Ivacaftor treatment and to determine if these data allow prediction of Ivacaftor responsiveness. Methods: We performed RNA-sequencing (RNA-seq) on PBMCs from CF patients and compared the transcriptomic changes before and after Ivacaftor treatments. Consensus clustering method is employed to stratify patients into sub-groups based on clinical responses post treatment, and determined differences in baseline gene expression. A random forest model is built to predict Ivacaftor responsiveness. Measurement and Main Results: We identified 239 genes that were significantly influenced by Ivacaftor in PBMC. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into “good” and “moderate” responders based on clinical response to Ivacraftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. Conclusions: For the first time, the present study demonstrates profound transcriptomic impacts of Ivafactor in CF patients PBMCs and successfully built a statistical model for predicting the clinical responsiveness to Ivacaftor prior to treatment.
2019-08-27 | GSE128723 | GEO
Project description:Elexacaftor/tezacaftor/ivacaftor (ETI) CFTR modulator therapy has led to rapid and substantial improvements in cystic fibrosis (CF) airway disease. Underlying molecular and cellular mechanisms, long-term efficacy, and ability to reverse airway epithelial remodeling in established disease remain unclear. Longitudinal nasal brushes from an adult CF cohort were used to evaluate gene expression, cellular composition, stem cell function, and microbiome changes at baseline and at six months and two years after ETI. The baseline to six month span showed a massive downregulation of extensive neutrophilic inflammatory gene expression programs that correlated with increased pulmonary function and decreased sinusitis. Primary airway epithelial stem cell cultures from matched donor samples showed partially improved differentiation and barrier capacity at six months. Although clinical outcomes remained stable during the six month to two year span, transcriptional changes revealed a resurgence of baseline inflammatory programs. Time course gene expression was consistent with ongoing normalization of epithelial remodeling. Relative abundance of Pseudomonas also decreased during the time course. These data suggest that ETI rectifies inflammation, epithelial remodeling, and bacterial infection in the airways, but resurgence of inflammatory gene expression may indicate ongoing inflammation, potentially presaging disease progression with long-term therapy.
2025-09-03 | GSE306517 | GEO
Project description:Using mouse models of airway inflammation, we identified a causal link between the microbiota-dependent bile acid isolithocholic acid and protection against lung immunopathology. We further found that this protection involves Sphingosine-1-phosphate receptor 2–dependent metabolic rewiring of alveolar macrophages as a key mechanism. Collectively, our findings demonstrate that isolithocholic acid, a microbiota-derived bile acid, can ameliorate lung inflammation through previously unrecognized pathways, highlighting its therapeutic potential—and that of its derivatives—in lung disease.
2025-11-13 | GSE307734 | GEO