Featured
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Article
| Open AccessBridging of host-microbiota tryptophan partitioning by the serotonin pathway in fungal pneumonia
Serotonin regulates mood as well as intestinal homeostasis, but its role in lung immune homeostasis is less clear. Here, Renga et al. show that serotonin regulates immune and microbial metabolic functions in respiratory pneumonia, beyond its mood regulatory function, by modulating tryptophan metabolism in the cystic fibrosis lung.
- Giorgia Renga
- , Fiorella D’Onofrio
- & Luigina Romani
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Perspective
| Open AccessFuture therapies for cystic fibrosis
The cystic fibrosis landscape has changed dramatically over the last few decades, with improvements in patient quality of life, prognosis and predicted survival. In part, this is related to the availability of novel CFTR modulator drugs, although prior advances in symptom-directed therapies and diagnosis had already led to substantial improvements. However, the authors, part of a national CF focused group, recognize that more needs to be done and outline their considerations on research priorities in this perspective.
- Lucy Allen
- , Lorna Allen
- & Jane C. Davies
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Article
| Open AccessSARS-CoV-2 viral entry and replication is impaired in Cystic Fibrosis airways due to ACE2 downregulation
Patients with cystic fibrosis are not reporting particularly sever outcomes upon SARS-CoV-2 infection. Here, the authors demonstrate decreased ACE2 levels is cystic fibrosis airway epithelia associated with impaired viral entry and replication.
- Valentino Bezzerri
- , Valentina Gentili
- & Marco Cipolli
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Article
| Open AccessPEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis
Currently, there is a lack of effective drugs for the treatment of pulmonary fibrosis. Here, the authors reveal a novel role of PEAR1 in fibroblast activation and demonstrate that activating PEAR1 by monoclonal antibodies might be a promising therapeutic approach for pulmonary fibrosis.
- Yan Geng
- , Lin Li
- & Xuemei Fan
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Article
| Open AccessA multimodal iPSC platform for cystic fibrosis drug testing
Hundreds of mutations in the gene CFTR lead to cystic fibrosis and represent a challenge to developing therapeutics. Here, authors demonstrate the ability of airway cells derived from human iPSCs to model genotype-specific CFTR function as well as pharmacologic rescue of disease causing mutations.
- Andrew Berical
- , Rhianna E. Lee
- & Finn J. Hawkins
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Article
| Open AccessGene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy
The W1282X nonsense mutation in the CFTR gene causes cystic fibrosis by reducing its mRNA and functional protein levels. Here the authors developed antisense-oligonucleotide cocktails that restore CFTR protein function by gene-specific stabilization of CFTR mRNA.
- Young Jin Kim
- , Tomoki Nomakuchi
- & Adrian R. Krainer
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Article
| Open AccessCFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway
Currently, there is no therapy for patients with cystic fibrosis caused by nonsense mutations. Here the authors show that CFTR mRNAs with nonsense codons are predominantly degraded by the SMG6-mediated branch of the NMD pathway, providing potential therapeutic strategies for the devastating disease.
- Edward J. Sanderlin
- , Melissa M. Keenan
- & Lulu Huang
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Article
| Open AccessEpigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
Muco-obstructive lung diseases are characterised by airway macrophage (AM) populations which may have epigenetic changes. Here using a mouse model the authors show epigenetic alteration of AMs with changes in LPS response, phagocytosis and efferocytosis similar to culture with mucus in vitro.
- Joschka Hey
- , Michelle Paulsen
- & Marcus A. Mall
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Article
| Open AccessA small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion
Premature termination codons can cause early translation termination and lead to disease. Here the authors perform a screen to identify compounds with readthrough activity and show that these reduce eRF1 levels to suppress premature termination associated with cystic fibrosis.
- Jyoti Sharma
- , Ming Du
- & David M. Bedwell
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Article
| Open AccessSub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples
The analysis of metabolites offers promises in biomarker discovery. Here the authors demonstrate the metabolomics analysis of sub-nanoliter samples using triboelectric nanogenerator inductive nanoelectrospray ionization, which they apply to exhaled breath condensate from cystic fibrosis patients and mesenchymal stromal cells.
- Yafeng Li
- , Marcos Bouza
- & Facundo M. Fernández
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Article
| Open AccessAllele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing
Cystic fibrosis is caused by mutations in the CFTR chloride channel. Here, the authors develop a gene therapy approach using the programmable nuclease AsCas12a to correct a splicing mutation in CFTR, and show efficient repair of the mutation and recovery of CFTR function in patient-derived organoids and airway epithelial cells.
- Giulia Maule
- , Antonio Casini
- & Anna Cereseto
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Article
| Open AccessPhenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells
Personalized approaches to diagnosis and treatment monitoring could improve the management of cystic fibrosis patients. Here the authors show that multiscale differential dynamic microscopy can assess changes in cilia beating dynamics and coordination in patient-derived airway epithelial cells, in response to different CFTR-modulating drugs, in a patient-specific manner.
- M. Chioccioli
- , L. Feriani
- & P. Cicuta
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Article
| Open AccessAirway surface liquid pH is not acidic in children with cystic fibrosis
Modulation of airway surface liquid pH has been proposed as a therapy for cystic fibrosis, but whether pH is indeed altered in cystic fibrosis is controversial. Here, the authors develop a novel fibre-optic based pH measurement technology, and show that pH is not altered in children with cystic fibrosis.
- André Schultz
- , Ramaa Puvvadi
- & Stephen M. Stick
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Article
| Open AccessCystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens
Cystic fibrosis is caused by mutations in the CFTR chloride channel, leading to reduced airway surface liquid secretion. Here the authors show that exposure to bacteria triggers secretion in wild-type but not in pig models of cystic fibrosis, suggesting an impaired response to pathogens contributes to infection.
- Xiaojie Luan
- , George Belev
- & Juan P. Ianowski
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Article
| Open AccessA mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis
In patients with cystic fibrosis, IL-9 signalling is increased. The authors describe an inflammatory loop in which IL-9 produced by Th9 cells drives mast cells to produce IL-2, resulting in ILC2 cell activation, and show inhibition of this loop with blocking antibodies to IL-9 in a mouse model of pulmonary infection.
- Silvia Moretti
- , Giorgia Renga
- & Luigina Romani