Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation

The Lancet Respiratory Medicine, Journal Year: 2023, Volume and Issue: 11(8), P. 709 - 725

Published: May 19, 2023

Language: Английский

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SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl− concentration

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 25, 2024

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play role in this process. Pathogens could interfere with transepithelial Cl − transport via impairment cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, pathological effects SARS-CoV-2 E protein on function, robust inflammatory response remain to be elucidated. Here, we have demonstrated that down-regulated expression tight junctional proteins, leading disruption barrier. In addition, triggered activation Toll-like receptor (TLR) 2/4 downstream c-Jun N-terminal kinase (JNK) signaling, resulting an increased intracellular concentration ([Cl ] i ) up-regulating phosphodiesterase 4D (PDE4D) cells. This elevated [Cl contributed heightened inflammation through promoting phosphorylation serum/glucocorticoid regulated 1 (SGK1). Moreover, blockade SGK1 or PDE4 alleviated induced by protein. Overall, these findings provide novel insights into pathogenic damage ongoing during infection.

Language: Английский

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SARS-CoV-2 spike protein receptor binding domain promotes IL-6 and IL-8 release via ATP/P2Y2 and ERK1/2 signaling pathways in human bronchial epithelia

Molecular Immunology, Journal Year: 2024, Volume and Issue: 167, P. 53 - 61

Published: Feb. 14, 2024

Language: Английский

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Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 23, 2024

Abstract SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response the host airway. This state involves activation of signaling NFκB, unexpectedly, ENaC, epithelial sodium channel. Post-infection inflammation may also contribute "Long COVID"/PASC. Enhanced NFκB ENaC marks airway suffering from cystic fibrosis, life-limiting proinflammatory genetic disease due inactivating mutations CFTR gene. We therefore hypothesized that might similarly be inhibition SARS-CoV-2 spike protein, both signaling. used western blot electrophysiological techniques, an organoid model normal epithelia, differentiated on air–liquid-interface (ALI). found protein expression cAMP-activated chloride channel activity were lost when epithelium was exposed proteins. As hypothesized, absence led TNFα/NFκB α γ ENaC. had previously shown cardiac glycoside drugs digoxin, digitoxin ouabain blocked interaction ACE2. Consistently, addition 30 nM concentrations drugs, prevented loss activity. ACE2 co-immunoprecipitate basal cells epithelia. Thus spike-dependent involve as bridge between Spike CFTR. In addition, exposure epithelia resulted failure endosomal recycling return plasma membrane. Thus, recovery mechanism for Finally, we authentic virus infection induced which rescued ouabain. Based experiments with this small comparisons 16HBE14o- other cell types expressing CFTR, predict mediated thus fibrosis-like clinical phenotype. To our knowledge is first time has been experimentally traced subjects contribution

Language: Английский

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The breathtaking world of human respiratory in vitro models: Investigating lung diseases and infections in 3D models, organoids, and lung‐on‐chip

European Journal of Immunology, Journal Year: 2024, Volume and Issue: 54(3)

Published: Feb. 15, 2024

Abstract The COVID‐19 pandemic illustrated an urgent need for sophisticated, human tissue models to rapidly test and develop effective treatment options against this newly emerging severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Thus, in particular, the last 3 years faced extensive boost pulmonary model development. Nowadays, 3D models, organoids lung‐on‐chip, perfusion, or precision‐cut lung slices are used study complex research questions primary cells. These provide physiologically relevant systems studying SARS‐CoV‐2 and, of course, other pathogens, but they are, too, suited pathologies, such as CF, chronic obstructive disease, asthma, more detail terms viral infection. With these cornerstone has been laid further advancing organs by, example, inclusion several immune cell types humoral components, combination with microfluidic organ‐on‐chip devices, standardization harmonization devices reliable reproducible drug vaccine testing high throughput.

Language: Английский

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COVID-19 Biogenesis and Intracellular Transport

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4523 - 4523

Published: Feb. 24, 2023

SARS-CoV-2 is responsible for the COVID-19 pandemic. The structure of and most its proteins have been deciphered. enters cells through endocytic pathway perforates endosomes’ membranes, (+) RNA appears in cytosol. Then, starts to use protein machines host their membranes biogenesis. generates a replication organelle reticulo-vesicular network zippered endoplasmic reticulum double membrane vesicles. viral start oligomerize are subjected budding within ER exit sites, virions passed Golgi complex, where glycosylation appear post-Golgi carriers. After fusion with plasma membrane, glycosylated secreted into lumen airways or (seemingly rarely) space between epithelial cells. This review focuses on biology SARS-CoV-2’s interactions transport Our analysis revealed significant number unclear points related intracellular SARS-CoV-2-infected

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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Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15518 - 15518

Published: Oct. 24, 2023

The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly search candidates that interact with various SARS-CoV-2 receptors. These involve use of computer simulations and computational algorithms predict potential interaction target primary receptors targeted by include RNA polymerase, main protease, spike protein, ACE2 receptor, transmembrane protease serine 2 (TMPRSS2). identified several promising candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, Camostat Mesylate, among others. offers advantages, ability screen large number relatively short amount time, thereby reducing time cost involved traditional methods. Additionally, allow prediction binding affinity receptors, providing insight into their efficacy. This study is aimed at assessing useful contributions application instruments It further highlights some advantages limitations these studies, revealing complementary experimental validation ensure efficacy safety candidates.

Language: Английский

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Humoral and cell-mediated immune responses to BNT162b2 vaccine against SARS-CoV-2 in people with cystic fibrosis

Vaccine, Journal Year: 2023, Volume and Issue: 41(28), P. 4114 - 4120

Published: May 22, 2023

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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