CD36 mediates SARS-CoV-2-envelope-protein-induced platelet activation and thrombosis DOI Creative Commons

Zihan Tang,

Yanyan Xu, Yun Tan

et al.

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

Published: Aug. 21, 2023

Abstract Aberrant coagulation and thrombosis are associated with severe COVID-19 post-SARS-CoV-2 infection, yet the underlying mechanism remains obscure. Here we show that serum levels of SARS-CoV-2 envelope (E) protein disorders patients, intravenous administration E is able to potentiate in mice. Through pull-down mass spectrometry, find CD36, a transmembrane glycoprotein, directly binds mediates hyperactivation human mouse platelets through p38 MAPK-NF-κB signaling pathway. Conversely, pharmacological blockade CD36 or notably attenuates platelet activation induced by protein. Similarly, genetic deficiency , as well inhibition mice, significantly diminishes protein-induced thrombotic events. Together, our study reveals critical role for CD36-p38 axis hyperactivity, which could serve an actionable target developing therapies against aberrant events related severity mortality COVID-19.

Language: Английский

Ozone based inactivation and disinfection in the pandemic time and beyond: Taking forward what has been learned and best practice DOI Open Access
Yamei Cai, Yaqian Zhao, Asheesh Kumar Yadav

et al.

The Science of The Total Environment, Journal Year: 2022, Volume and Issue: 862, P. 160711 - 160711

Published: Dec. 7, 2022

Language: Английский

Citations

39
SARS-COV-2 viroporins activate the NLRP3-inflammasome by the mitochondrial permeability transition pore DOI Creative Commons
Joseph W. Guarnieri, Alessia Angelin, Deborah G. Murdock

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 20, 2023

Background Compared to healthy controls, severe COVID19 patients display increased levels of activated NLRP3-inflammasome (NLRP3-I) and interleukin (IL)-1β. SARS-CoV-2 encodes viroporin proteins E Orf3a(2-E+2-3a) with homologs SARS-CoV-1, 1-E+1-3a, which elevate NLRP3-I activation; by an unknown mechanism. Thus, we investigated how 2-E+2-3a activates the better understand pathophysiology COVID-19. Methods We generated a polycistronic expression-vector co-expressing from single transcript. To elucidate NLRP3-I, reconstituted in 293T cells used THP1-derived macrophages monitor secretion mature IL-1β. Mitochondrial physiology was assessed using fluorescent microscopy plate reader assays, release mitochondrial DNA (mtDNA) detected cytosolic-enriched fractions Real-Time PCR. Results Expression cytosolic Ca++ elevated Ca++, taken up through MCUi11-sensitive calcium uniporter. Increased stimulated NADH, reactive oxygen species (mROS) production mtDNA into cytosol. displayed Increasing antioxidant defenses via treatment MnTBAP or genetic expression mCAT abolished elevation mROS, levels, NLRP3-activated-IL-1β. The 2-E+2-3a-induced NLRP3-activated-IL-1β were absent lacking blocked treated mitochondrial-permeability-pore(mtPTP)-specific inhibitor NIM811. Conclusion Our findings revealed that mROS NIM811-sensitive mitochondrial-permeability-pore(mtPTP), activating inflammasome. Hence, interventions targeting mtPTP may mitigate severity COVID-19 cytokine storms.

Language: Английский

Citations

33
NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis DOI
Nicola Potere,

Evan Garrad,

Yogendra Kanthi

et al.

Cardiovascular Research, Journal Year: 2023, Volume and Issue: 119(11), P. 2046 - 2060

Published: May 30, 2023

Abstract Immunothrombosis—immune-mediated activation of coagulation—is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines the interleukin (IL)-1 family, IL-1β IL-18, induces pyroptotic cell death. Activation NLRP3 pathway also promotes immunothrombotic programs including release neutrophil extracellular traps tissue factor by leukocytes, prothrombotic responses platelets vascular endothelium. occurs patients with COVID-19 pneumonia. In preclinical models, blockade restrains COVID-19-like hyperinflammation pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety efficacy is approved for treatment hypoxaemic early signs hyperinflammation. non-selective inhibitor colchicine reduced hospitalization death a subgroup outpatients not COVID-19. Additional trials testing blockers are inconclusive or ongoing. We herein outline contribution to COVID-19-associated coagulopathy, review clinical evidence suggesting an engagement pathogenesis summarize current efforts target COVID-19, discuss challenges, unmet gaps, therapeutic potential that inflammasome-targeted strategies may provide inflammation-driven thrombotic disorders

Language: Английский

Citations

31
SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19 DOI Creative Commons
Joseph W. Guarnieri, Jeffrey Haltom, Yentli E. Soto Albrecht

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 204, P. 107170 - 107170

Published: April 12, 2024

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey metabolic pathways modulated by and confirmed their importance for propagation cataloging specific pathway inhibitors. This revealed that strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from oxidation through glycolysis pentose phosphate (PPP) to provide substrates viral biogenesis. also induces release DNA (mtDNA) activates innate immunity. restructuring energy metabolism is mediated part Orf8 Orf10 whose expression restructures nuclear (nDNA) mtDNA OXPHOS gene expression. These proteins likely alter epigenome, either directly altering histone modifications or modulating metabolite epigenome modification enzymes, potentially silencing contributing long-COVID.

Language: Английский

Citations

14
Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies DOI Creative Commons
Wen Ma, Songling Tang, Yao Peng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause morbidity and mortality critically ill patients. is characterized by hypoxaemic failure with diffuse pulmonary inflammation bilateral edema due to excessive alveolocapillary permeability patients non-cardiogenic diseases. Over past seven decades, our understanding pathology clinical characteristics evolved significantly, yet it an area active research discovery. highly heterogeneous, including diverse pathological causes, presentations, treatment responses, presenting challenge for clinicians researchers. this review, we comprehensively discuss latest advancements research, focusing on its heterogeneity, pathophysiological mechanisms, emerging therapeutic approaches, such as cellular therapy, immunotherapy, targeted therapy. Moreover, also examine COVID-19-related corresponding approaches. face challenges posed offer hope improved patient outcomes. Further essential translate these findings into effective interventions personalized approaches ARDS, ultimately leading better outcomes suffering from ARDS.

Language: Английский

Citations

1
Is There a Link Between the Pathogenic Human Coronavirus Envelope Protein and Immunopathology? A Review of the Literature DOI Creative Commons
Dewald Schoeman, Burtram C. Fielding

Frontiers in Microbiology, Journal Year: 2020, Volume and Issue: 11

Published: Sept. 3, 2020

Since the severe acute respiratory syndrome (SARS) outbreak in 2003, human coronaviruses (hCoVs) have been identified as causative agents of tract infections. Two more hCoV outbreaks since occurred, most recent being SARS-CoV-2, agent coronavirus disease 2019 (COVID-19). The clinical presentation SARS and MERS is remarkably similar to COVID-19, with hyperinflammation causing a form some patients. Previous studies show that expression SARS-CoV E protein associated hyperinflammatory response could culminate distress (ARDS), potentially fatal complication. This immune-mediated damage largely caused by cytokine storm, which induced significantly elevated levels inflammatory cytokines interleukin (IL)-1β IL-6, are partly mediated protein. interaction between host protein, syntenin, well viroporin function E, linked this dysregulation. review aims compare virulent hCoVs specific focus on cause immunopathology. also proposes inhibition IL-1β IL-6 cases can improve patient outcome.

Language: Английский

Citations

63
Alkaloids as Potential Phytochemicals against SARS-CoV-2: Approaches to the Associated Pivotal Mechanisms DOI Open Access
Mohammad Bagher Majnooni, Sajad Fakhri, Gholamreza Bahrami

et al.

Evidence-based Complementary and Alternative Medicine, Journal Year: 2021, Volume and Issue: 2021, P. 1 - 21

Published: May 13, 2021

Since its inception, the coronavirus disease 2019 (COVID-19) pandemic has infected millions of people around world. Therefore, it is necessary to find effective treatments against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), as viral source COVID-19. Alkaloids are one most widespread plant-derived natural compounds with prominent antiviral effects. Accordingly, these phytochemicals have been promising candidates towards discovering for shown potential anti-SARS-CoV activities via inhibiting pathogenesis-associated targets Coronaviridae family that required virus life cycle. In current study, chemistry, plant sources, and effects alkaloids, well their anti-SARS-CoV-2 effect related mechanisms, reviewed an treatment

Language: Английский

Citations

48
pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein DOI
João Medeiros‐Silva, Noah H. Somberg, Harrison K. Wang

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(15), P. 6839 - 6850

Published: April 5, 2022

The envelope (E) protein of the SARS-CoV-2 virus is a membrane-bound viroporin that conducts cations across endoplasmic reticulum Golgi intermediate compartment (ERGIC) membrane host cell to cause pathogenicity. structure closed state E transmembrane (TM) domain, ETM, was recently determined using solid-state NMR spectroscopy. However, how channel pore opens mediate cation transport unclear. Here, we use 13C and 19F spectroscopy investigate conformation dynamics ETM at acidic pH in presence calcium ions, which mimic ERGIC lysosomal environment experienced by cell. Acidic ions increased conformational disorder N- C-terminal residues also water accessibility protein, indicating lumen has become more spacious. contains three regularly spaced phenylalanine (Phe) center peptide. spectra para-fluorinated Phe20 Phe26 indicate both exhibit two sidechain conformations, coexist within each channel. These Phe conformations differ their accessibility, lipid contact, dynamics. Channel opening Ca2+ increases population dynamic lipid-facing conformation. results suggest an intricate aromatic network regulates pore. This may be target for inhibitors against related coronaviruses.

Language: Английский

Citations

36
Inflammasomes and IL-1 family cytokines in SARS-CoV-2 infection: from prognostic marker to therapeutic agent DOI Open Access
Jozefien Declercq, Elisabeth De Leeuw, Bart N. Lambrecht

et al.

Cytokine, Journal Year: 2022, Volume and Issue: 157, P. 155934 - 155934

Published: June 7, 2022

Language: Английский

Citations

30
SARS-CoV-2 Envelope Protein Forms Clustered Pentamers in Lipid Bilayers DOI Open Access
Noah H. Somberg, Westley W. Wu, João Medeiros‐Silva

et al.

Biochemistry, Journal Year: 2022, Volume and Issue: 61(21), P. 2280 - 2294

Published: Oct. 11, 2022

The SARS-CoV-2 envelope (E) protein is a viroporin associated with the acute respiratory symptoms of COVID-19. E forms cation-selective ion channels that assemble in lipid membrane endoplasmic reticulum Golgi intermediate compartment. channel activity linked to inflammatory response host cell virus. Like many viroporins, thought oligomerize well-defined stoichiometry. However, attempts determine stoichiometry have led inconclusive results and suggested mixtures oligomers whose exact nature might vary detergent used. Here, we employ 19F solid-state nuclear magnetic resonance centerband-only detection exchange (CODEX) technique oligomeric number E's transmembrane domain (ETM) bilayers. CODEX equilibrium value, which corresponds inverse number, indicates ETM assembles into pentamers bilayers, without any detectable fraction low-molecular-weight oligomers. Unexpectedly, at high peptide concentrations presence phosphatidylinositol, data indicate more than five spins are within distance about 2 nm, suggesting cluster bilayer. Monte Carlo simulations take account peptide–peptide peptide–lipid interactions yielded pentamer clusters reproduced data. This supramolecular organization likely important for E-mediated virus assembly budding function protein.

Language: Английский

Citations

29