SARS-CoV-2 viral entry and replication is impaired in Cystic Fibrosis airways due to ACE2 downregulation

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 10, 2023

Abstract As an inherited disorder characterized by severe pulmonary disease, cystic fibrosis could be considered a comorbidity for coronavirus disease 2019. Instead, current clinical evidence seems to heading in the opposite direction. To clarify whether host factors expressed Cystic Fibrosis epithelia may influence 2019 progression, here we describe expression of SARS-CoV-2 receptors primary airway epithelial cells. We show that angiotensin converting enzyme 2 (ACE2) and localization are regulated Transmembrane Conductance Regulator (CFTR) channel. Consistently, our results indicate dysfunctional CFTR channels alter susceptibility infection, resulting reduced viral entry replication Depending on pattern ACE2 expression, spike (S) protein induced high levels Interleukin 6 healthy donor-derived cells, but very weak response Collectively, these data support condition at least partially protecting from infection.

Language: Английский

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Functional Consequences of CFTR Interactions in Cystic Fibrosis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3384 - 3384

Published: March 16, 2024

Cystic fibrosis (CF) is a fatal autosomal recessive disorder caused by the loss of function mutations within single gene for Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR chloride channel that regulates ion and fluid transport across various epithelia. The discovery as CF its cloning in 1989, coupled with extensive research went into understanding underlying biological mechanisms CF, have led to development revolutionary therapies we see today. highly effective modulator increased survival rates patients shifted epidemiological landscape disease prognosis. However, differential effect modulators among presence non-responders ineligible underscore need develop specialized customized significant number patients. Recent advances structure, expression, defined cellular compositions will aid developing more precise therapies. As lifespan continues increase, it becoming critical clinically address extra-pulmonary manifestations improve quality life In-depth analysis molecular signature different organs at transcriptional post-transcriptional levels rapidly advancing help etiological causes variability precision medicine CF. In this review, provide an overview disease, leading characterization modulators. later sections review delve key findings derived from single-molecule single-cell-level analyses CFTR, followed exploration disease-relevant protein complexes may ultimately define course disease.

Language: Английский

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A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(7), P. 1593 - 1603

Published: July 9, 2024

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains clinically untapped target. Nsp13 is helicase responsible unwinding double-stranded RNA during viral replication and essential propagation. Like other helicases, has two active sites: nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) nucleic acid channel unwinds or DNA. Targeting helicases with small molecules, as well the identification of ligand pockets, have been ongoing challenges, partly due flexible nature these proteins. Here, we use virtual screen identify ligands from collection used drugs. We find known ion inhibitor, IOWH-032, inhibits dual ATPase activities at low micromolar concentrations. Kinetic assays, along computational mutational analyses, indicate IOWH-032 interacts interface, leading displacement substrate, but not bound ATP. Evaluation microbial superfamilies reveals it selective Nsp13. Furthermore, against mutants representative observed variants. Overall, this work provides new inhibitor rationale observation lowers loads in human cells, setting stage discovery potent modulators.

Language: Английский

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CFTR Inhibitors Display In Vitro Antiviral Activity against SARS-CoV-2

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 776 - 776

Published: Feb. 28, 2023

Several reports have indicated that SARS-CoV-2 infection displays unexpected mild clinical manifestations in people with cystic fibrosis (pwCF), suggesting CFTR expression and function may be involved the life cycle. To evaluate possible association of activity replication, we tested antiviral two well-known inhibitors (IOWH-032 PPQ-102) wild type (WT)-CFTR bronchial cells. replication was inhibited by IOWH-032 treatment, an IC50 4.52 μM, PPQ-102, 15.92 μM. We confirmed this effect on primary cells (MucilAirTM wt-CFTR) using 10 μM IOWH-032. According to our results, inhibition can effectively tackle infection, might play important role revealing new perspectives mechanisms governing both normal CF individuals, as well leading potential novel treatments.

Language: Английский

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Divergent responses to SARS-CoV-2 infection in bronchial epithelium with pre-existing respiratory diseases

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 111999 - 111999

Published: Feb. 12, 2025

Pre-existing respiratory diseases may influence coronavirus disease (COVID-19) susceptibility and severity. However, the molecular mechanisms underlying airway epithelial response to severe acute syndrome 2 (SARS-CoV-2) infection severity in patients with chronic remain unelucidated. Using an vitro model of differentiated primary bronchial cells, we aimed investigate SARS-CoV-2 pre-existing cystic fibrosis (CF) obstructive pulmonary (COPD). Our study revealed reduced CF COPD epithelia SARS-CoV-2, relative that healthy controls. Mechanistically, transmembrane serine protease (TMPRSS2) activity potentially contributed this resistance epithelium. Upregulated complement inflammatory pathways primed antiviral state prior infection. Analysis a COVID-19 patient cohort validated our findings, correlating specific markers (IP-10, SERPINA1, CFB) This elucidates pathogenesis identifies potential biomarkers for clinical monitoring.

Language: Английский

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Inflammation and epithelial–mesenchymal transition in a CFTR‐depleted human bronchial epithelial cell line revealed by proteomics and human organ‐on‐a‐chip

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene, leading to chronic, unresolved inflammation of airways due uncontrolled recruitment polymorphonuclear leukocytes (PMNs). Evidence indicates that loss‐of‐function, addition promoting pro‐inflammatory phenotype, associated with an increased risk developing cancer, suggesting can exert tumor‐suppressor functions. Three‐dimensional (3D) vitro culture models, such as lung airway‐on‐a‐chip, be suitable for studying PMN recruitment, well events cancerogenesis, epithelial cell invasion and migration, CF. To gather insight into pathobiology we generated CFTR‐knockout (KO) clones 16HBE14o‐ human bronchial line CRISPR/Cas9 gene editing, performed comparative proteomic analysis these their wild‐type (WT) counterparts. Systematic signaling pathway CFTR‐KO revealed modulation inflammation, epithelial–mesenchymal transition. Using latest‐generation organ‐on‐a‐chip microfluidic platform, confirmed enhanced endothelial layer. Thus, dysfunctional affects multiple pathways airway epithelium ultimately contribute sustained cancerogenesis

Language: Английский

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Advances of CRISPR-Cas13 system in COVID-19 diagnosis and treatment

Genes & Diseases, Journal Year: 2022, Volume and Issue: 10(6), P. 2414 - 2424

Published: Dec. 27, 2022

The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has resulted in over 570 million infections and 6 deaths worldwide. Early detection quarantine are essential to arrest spread highly contagious COVID-19. High-risk groups, such as older adults individuals with comorbidities, can present symptoms, including pyrexia, pertussis, distress syndrome, on SARS-CoV-2 infection that prove fatal, demonstrating a clear need for high-throughput sensitive platforms detect eliminate SARS-CoV-2. CRISPR-Cas13, an emerging CRISPR system targeting RNA high specificity efficiency, recently drawn much attention COVID-19 diagnosis treatment. Here, we summarized current research progress CRISPR-Cas13 treatment highlight challenges future directions effectively counteracting

Language: Английский

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Chloride channels in the lung: Challenges and perspectives for viral infections, pulmonary arterial hypertension, and cystic fibrosis

Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 237, P. 108249 - 108249

Published: July 23, 2022

Fine control over chloride homeostasis in the lung is required to maintain membrane excitability, transepithelial transport as well intra- and extracellular ion water homeostasis. Over last decades, a growing number of channels transporters have been identified cells pulmonary vasculature respiratory tract. The importance these proteins underpinned by fact that impairment their physiological function associated with functional dysregulation, structural remodeling, or hereditary diseases lung. This paper reviews field discusses disease processes such viral infections including SARS-CoV- 2, arterial hypertension, cystic fibrosis asthma. Although become hot research topic recent years, remarkably few them targeted pharmacological agents. As such, we complement putative pathophysiological role here summary therapeutic potential.

Language: Английский

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TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis

Journal of Innate Immunity, Journal Year: 2023, Volume and Issue: 15(1), P. 629 - 646

Published: Jan. 1, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, utilizes receptor binding domain (RBD) of spike glycoprotein to interact with angiotensin (Ang)-converting enzyme (ACE2). Altering ACE2 levels may affect entry SARS-CoV-2 and recovery from COVID-19. Decreased cell surface density leads increased local Ang II contribute mortality resulting lung injury fibrosis during Studies published early the COVID-19 pandemic reported that people cystic (PwCF) had milder symptoms, compared without CF. This finding was attributed elevated and/or treatment high efficiency CFTR modulators. Subsequent studies did not confirm these findings reporting variable effects gene mutations on levels. Transforming growth factor (TGF)-β signaling is essential infection dominates chronic immune response in leading pulmonary fibrosis. TGF-β1 a modifier associated more disease PwCF but its course unknown. To understand whether affects airway, we examined miRNAs their targets affecting pathogenesis TGF-β1. Small RNAseq micro(mi)RNA profiling identified pathways uniquely affected by TGF-β1, including those invasion, replication, host responses. inhibited expression miR-136-3p miR-369-5p mediated mechanism CF non-CF bronchial epithelial cells. were higher two models expressing most common CF-causing mutation F508del, controls mutation. After treatment, protein still CF, prevented modulator-mediated rescue F508del-CFTR function while modulators prevent inhibition Finally, reduced interaction between recombinant RBD lowering RBD. Our data demonstrate novel whereby cells modulate pathogenicity severity. By reducing levels, decrease into hindering due loss anti-inflammatory regenerative ACE2. above outcomes be modulated other, miRNA-mediated exerted responses, complex yet incompletely understood circuitry.

Language: Английский

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The impact of SARS-CoV-2 infection in patients with cystic fibrosis undergoing CFTR channel modulators treatment: a literature review

Respiratory Research, Journal Year: 2023, Volume and Issue: 24(1)

Published: Nov. 13, 2023

Abstract Several risk factors for Coronavirus-2019 (COVID-19) disease have been highlighted in clinical evidence. Among the various are advanced age, metabolic illness such as diabetes, heart disease, and diseases of respiratory system. Cystic Fibrosis (CF) is a rare with autosomal recessive transmission, characterised by lack synthesis CFTR channel protein, multi-organ symptoms mainly affecting tract recurrent pulmonary exacerbations. In view pathophysiological mechanisms, CF should be theory considered factor SARS-CoV2 or severe COVID-19. However, recent evidence seems to point opposite direction, suggesting that could protective against Possibly, presence function protein linked expression membrane glycoprotein ACE-2, key enzyme endocellular penetration SARS-CoV-2 related pathophysiology COVID-19 disease. Furthermore, modulating agents indirectly influence playing an important role restoring proper functioning mucociliary clearance microbiome host response infection. this review, authors attempt shed light on these associations issues not yet fully elucidated.

Language: Английский

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