Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(11), P. 6151 - 6157

Published: Aug. 6, 2020

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response fuels hyperinflammation thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how interacts with platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, sC5b-9 were detected in patients. Neutrophils patients yielded high TF expression released NETs carrying active TF. Treatment control platelet-rich generated TF-bearing induced activity HAECs. Thrombin or NETosis C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. serum activation vitro, consistent clinical samples. Complement C3 compstatin Cp40 disrupted neutrophils. In conclusion, provide a mechanistic basis for pivotal role immunothrombosis. This study supports strategies against severe acute respiratory syndrome 2 exploit inhibition.

Language: Английский

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COVID-19 and multiorgan failure: A narrative review on potential mechanisms

Journal of Molecular Histology, Journal Year: 2020, Volume and Issue: 51(6), P. 613 - 628

Published: Oct. 4, 2020

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in December 2019 form Wuhan, China leads to disease (COVID-19) pandemic. While the common cold symptoms are observed mild cases, COVID-19 is accompanied by multiorgan failure patients. involvement different organs patients results lengthening hospitalization duration and increasing mortality rate. In this review, we aimed investigate patients, particularly cases. Also, tried define potential underlying mechanisms SARS-CoV2 induced failure. multi-organ dysfunction characterized lung failure, liver kidney injury, cardiovascular disease, as well a wide spectrum hematological abnormalities neurological disorders. most important related direct indirect pathogenic features SARS-CoV2. Although presence angiotensin-converting enzyme 2, receptor lung, heart, kidney, testis, liver, lymphocytes, nervous system was confirmed, there controversial findings about observation RNA these organs. Moreover, organ may be cytokine storm, result increased levels inflammatory mediators, endothelial dysfunction, coagulation abnormalities, infiltration cells into Therefore, further investigations needed detect exact pathogenesis. Since several for clinicians, their knowledge help improve outcomes decrease rate morbidity.

Language: Английский

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The complement system in COVID-19: friend and foe?

JCI Insight, Journal Year: 2020, Volume and Issue: 5(15)

Published: June 18, 2020

Coronavirus disease 2019 (COVID-19), the caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and disruptive health crisis. COVID-19-related morbidity mortality have been attributed to an exaggerated immune response. The role of complement activation its contribution illness severity is being increasingly recognized. Here, we summarize current knowledge about interaction coronaviruses with system. We posit that (a) activate multiple pathways; (b) COVID-19 clinical features often resemble complementopathies; (c) combined effects activation, dysregulated neutrophilia, endothelial injury, hypercoagulability appear be intertwined drive COVID-19; (d) subset patients may genetic predisposition associated dysregulation; (e) these observations create basis for trials inhibitors life-threatening illness.

Language: Английский

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The Lectin Pathway of the Complement System—Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1566 - 1566

Published: Jan. 26, 2024

The complement system is the other major proteolytic cascade in blood of vertebrates besides coagulation–fibrinolytic system. Among three main activation routes complement, lectin pathway (LP) has been discovered latest, and it still subject intense research. Mannose-binding (MBL), collectins, ficolins are collectively termed as pattern recognition molecules (PRMs) LP, they responsible for targeting LP to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) effectors, while proteins (MAps) have regulatory functions. Two protease components, MASP-1 MASP-2, trigger activation, third component, MASP-3, involved function alternative (AP) complement. Besides their functions within system, certain components secondary (“moonlighting”) functions, embryonic development. They also contribute coagulation, some might tumor suppressing roles. Uncontrolled can progression many diseases (e.g., stroke, kidney diseases, thrombotic complications, COVID-19). In most cases, implicated. this review, we summarize history pathway, introduce describe its regulation, roles cascade, connections direct cellular effects. Special emphasis placed disease non-canonical components.

Language: Английский

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Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID

Med, Journal Year: 2024, Volume and Issue: 5(3), P. 239 - 253.e5

Published: Feb. 15, 2024

BackgroundLong COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is hallmark acute COVID-19 but has not been investigated as potential determinant long COVID.MethodsWe quantified series complement proteins, including markers activation regulation, in plasma samples healthy convalescent confirmed history SARS-CoV-2 age/ethnicity/sex/infection/vaccine-matched patients COVID.FindingsMarkers classical (C1s-C1INH complex), alternative (Ba, iC3b), terminal pathway (C5a, TCC) were significantly elevated COVID. These combination had receiver operating characteristic predictive power 0.794. Other proteins regulators also quantitatively different between Generalized linear modeling further revealed clinically tractable just four these markers, namely the fragments iC3b, TCC, Ba, C5a, 0.785.ConclusionsThese findings suggest biomarkers could facilitate currently available inhibitors be used to treat COVID.FundingThis work was funded by National Institute for Health Research (COV-LT2-0041), PolyBio Foundation, UK Dementia Institute.

Language: Английский

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COVID-19 and cardiovascular consequences: Is the endothelial dysfunction the hardest challenge?

Thrombosis Research, Journal Year: 2020, Volume and Issue: 196, P. 143 - 151

Published: Aug. 27, 2020

A Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has become a pandemic disease named Coronavirus Disease-19 (COVID-19) of epochal dimension. The clinical spectrum COVID-19 is wide, ranging from asymptomatic forms to severe pneumonia, sepsis and multiple organ dysfunction syndromes resulting in poor outcomes. Among the various consequences COVID-19, cardiovascular (CV) collapse appears most serious potentially lethal. On other hand, pre-existent CV comorbidities are also associated with higher mortality. reliable hypothetical pathogenetic mechanism for complications cardiac injury patients be sustained endothelial dysfunction, caused by interplay inflammation coagulation. In this review, we survey papers addressing issues related characterized enhanced lung microvascular loss, hypercytokinemia, hypoxemia thrombosis. We discuss about how virus-induced downregulation angiotensin converting enzyme-2 (ACE2) receptor, used enter host cell, could affect renin-angiotensin system, attempting clarify doubts use ACE inhibitors Angiotensin-II receptor blockers patients. Finally, point out delicate physiological homeostatic function endothelium, which turns into disastrous battlefield complex interaction between "cytokine coagulative storms", can irreparably compromised result systemic inflammatory complications.

Language: Английский

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The battle between host and SARS-CoV-2: Innate immunity and viral evasion strategies

Molecular Therapy, Journal Year: 2022, Volume and Issue: 30(5), P. 1869 - 1884

Published: Feb. 14, 2022

The SARS-CoV-2 virus, the pathogen causing COVID-19, has caused more than 200 million confirmed cases, resulting in 4.5 deaths worldwide by end of August, 2021. Upon detection infection pattern recognition receptors (PRRs), multiple signaling cascades are activated, which ultimately leads to innate immune response such as induction type I and III interferons, well other antiviral genes that together restrict viral spread suppressing different steps life cycle. Our understanding contribution system recognizing subsequently initiating a host an invasion been rapidly expanding from 2020. Simultaneously, evolved evasion strategies escape surveillance for successful replication. In this review, we will address current knowledge immunity context highlight recent advances mechanisms evades host's defense system.

Language: Английский

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The anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 118, P. 110081 - 110081

Published: March 28, 2023

Language: Английский

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Long COVID: Complications, Underlying Mechanisms, and Treatment Strategies

Archives of Microbiology & Immunology, Journal Year: 2023, Volume and Issue: 07(02)

Published: Jan. 1, 2023

Long Covid is one of the most prevalent and puzzling conditions that arose with pandemic. Covid-19 infection generally resolves within several weeks but some experience new or lingering symptoms. Though there no formal definition for such symptoms CDC boadly describes long as persons having a wide range new, recurring sustained health issues four more after first being infected SARS-CoV2. The WHO defines manifestation from "probable confirmed" start approximately 3 months onset acute last than 2 months. Numerous studies have looked at implications on various organs. Many specific mechanisms been proposed changes. In this article, we provide an overview main by which induces end-organ damage in recent research studies. We also review treatment options, current clinical trials, other potential therapeutic avenues to control followed information about effect vaccination Covid. Lastly, discuss questions knowledge gaps present understanding believe effects has quality life, future life expectancy are required better understand eventually prevent treat disease. acknowledge not limited those article it may affect offspring therefore, deem important identify prognostic targets condition.

Language: Английский

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Complement and COVID-19: Three years on, what we know, what we don't know, and what we ought to know

Immunobiology, Journal Year: 2023, Volume and Issue: 228(3), P. 152393 - 152393

Published: May 1, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus was identified in China 2019 as the causative agent of COVID-19, and quickly spread throughout world, causing over 7 million deaths, which occurred prior to introduction first vaccine. In following discussion, while recognising that complement is just one many players we focus on relationship between COVID-19 disease, with limited digression into directly-related areas such complement, kinin release, coagulation. Prior outbreak, an important role for diseases had been established. Subsequently, multiple investigations patients confirmed dysregulation likely be a major driver disease pathology, some, if not all, patients. These data fuelled evaluation complement-directed therapeutic agents small patient cohorts, claims significant beneficial effect. As yet, these early results have reflected larger clinical trials, posing questions who treat, appropriate time duration treatment, optimal target treatment. While control pandemic has achieved through global scientific medical effort comprehend etiology extensive SARS-CoV-2 testing quarantine measures, vaccine development, improved therapy, possibly aided by attenuation dominant strains, it yet over. this review, summarise complement-relevant literature, emphasise its main conclusions, formulate hypothesis involvement COVID-19. Based make suggestions how any future outbreak might better managed order minimise impact

Language: Английский

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