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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Local complement activation and modulation in mucosal immunity

Mucosal Immunology, Journal Year: 2024, Volume and Issue: 17(4), P. 739 - 751

Published: June 4, 2024

Language: Английский

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Longitudinal analysis of the lung proteome reveals persistent repair months after mild to moderate COVID-19

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(7), P. 101642 - 101642

Published: July 1, 2024

In order to assess homeostatic mechanisms in the lung after COVID-19, changes protein signature of bronchoalveolar lavage from 45 patients with mild moderate disease at three phases (acute, recovery, and convalescent) are evaluated over a year. During acute phase, inflamed uninflamed phenotypes characterized by expression tissue repair host defense response molecules. With inflammatory fibrogenic mediators decline clinical symptoms abate. However, 9 months, quantified radiographic abnormalities resolve majority patients, yet compared healthy persons, all showed ongoing activation cellular processes depression renin-kallikrein-kinin, coagulation, complement systems. This dissociation prolonged reparative symptom resolution suggests that occult disruption proteome is underrecognized may be relevant recovery other serious viral pneumonias.

Language: Английский

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The complement system: A key player in the host response to infections

European Journal of Immunology, Journal Year: 2024, Volume and Issue: 54(11)

Published: Aug. 27, 2024

Abstract Infections are one of the most significant healthcare and economic burdens across world as underscored by recent coronavirus pandemic. Moreover, with increasing incidence antimicrobial resistance, there is an urgent need to better understand host–pathogen interactions design effective treatment strategies. The complement system a key arsenal host defense response pathogens bridges both innate adaptive immunity. However, in contest between mechanisms, not always victorious. Pathogens have evolved several approaches, including co‐opting regulators evade complement‐mediated killing. Furthermore, deficiencies proteins, genetic therapeutic, can lead inefficient pathogen eradication, rendering more susceptible certain infections. On other hand, overwhelming infection provoke fulminant activation uncontrolled inflammation potentially fatal tissue organ damage. This review presents overview critical aspects complement‐pathogen during discusses perspectives on designing therapies mitigate dysfunction limit injury.

Language: Английский

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Enhanced complement activation and MAC formation accelerates severe COVID-19

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Sept. 16, 2024

Emerging evidence indicates that activation of complement system leading to the formation membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3

Language: Английский

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Tocilizumab modulates the activity of the classical and alternative complement pathways in rheumatoid arthritis patients

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 30, 2025

Background Tocilizumab (TCZ) is a monoclonal antibody that neutralizes interleukin (IL)-6 and indicated for diseases characterized by markedly elevated inflammatory markers, such as rheumatoid arthritis (RA). The complement system has been implicated in the etiopathogenesis of RA. Objective To evaluate effect systemic IL-6 inhibition on pathways functional activity RA patients treated with TCZ. Desing Prospective non-interventional study. Methods Twenty-seven included TOCRIVAR study who received TCZ (8mg/kg IV/q4w) were evaluated at baseline weeks 12, 24 52 treatment. Disease activity, assessed composite indices, acute phase reactants, new-generation assays three pathways, was each follow-up visit. Multivariable linear mixed models used to determine changes cascades over time. Results After adjustment disease basal levels classical alternative decreased significantly after pathway remained significant weeks. decrease 12 24, but not week had no lectin cascade throughout follow-up. Conclusion reduces regardless improvement activity. This finding may contribute better understanding mechanisms which blockade patients.

Language: Английский

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Identification of key regulatory genes in the pathogenesis of COVID-19 and sepsis: An observational study

Medicine, Journal Year: 2024, Volume and Issue: 103(22), P. e38378 - e38378

Published: May 31, 2024

Patients with severe COVID-19 and those sepsis have similar clinical manifestations. We used bioinformatics methods to identify the common hub genes in these 2 diseases. Two RNA-seq datasets from Gene Expression Omnibus were differentially expressed (DEGs) sepsis. These for analysis of functional enrichment; pathway analysis; identification associated transcription factors, metabolites, miRNAs; mapping protein–protein interaction networks. The major identified, validation assess value using receiver operating characteristic (ROC) curves. Analysis 800 DEGs sepsis, as well miRNAs, demonstrated that immune response had a key role both DLGAP5, BUB1, CDK1, CCNB1 , BUB1B most important genes. cohort indicated 5 significantly higher expression patients than corresponding controls, area under ROC curves ranged 0.832 0.981 0.840 0.930 tools DEGs, factors identified cohorts good or excellent diagnostic performance based on analysis, therefore potential use novel markers therapeutic targets.

Language: Английский

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Targeted Modulation of Redox and Immune Homeostasis in Acute Lung Injury Using a Thioether‐Functionalized Dendrimer

Small, Journal Year: 2024, Volume and Issue: 20(42)

Published: June 18, 2024

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions immune homeostasis in lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG developed, to scavenge both proinflammatory cytokines reactive oxygen species (ROS) restore during ALI treatment. The dendrimers are synthesized using efficient orthogonal thiol-ene "click" chemistry approach involves incorporating thioether moieties within dendritic architectures neutralize ROS. ROS scavenging manifests its capacity sequester cytokines. synergistic effects sequestering contribute remodeling homeostasis, along with modulation NLRP3-pyroptosis pathway. Treatment enhances therapeutic efficacy ALIs alleviating alveolar bleeding, reducing cell infiltration, suppressing release These results suggest a potent nanotechnological candidate for treatment ALIs, demonstrating great potential dendrimer-based nanomedicine pathologies.

Language: Английский

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Exploring the Action Mechanism and Validation of the Key Pathways of Dendrobium officinale Throat-clearing Formula for the Treatment of Chronic Pharyngitis Based on Network Pharmacology

Combinatorial Chemistry & High Throughput Screening, Journal Year: 2023, Volume and Issue: 27(3), P. 479 - 496

Published: Dec. 27, 2023

Aim: This study investigated the molecular action mechanism of a compound herb, also known as Dendrobium officinale throat-clearing formula (QYF), by using network pharmacology and animal experimental validation methods to treat chronic pharyngitis (CP). Methods: The active ingredients disease targets QYF were determined searching Batman-TCM GeneCards databases. Subsequently, drug-active ingredient-target protein-protein interaction networks constructed, core obtained through topology. Metascape database was screened, enriched with Gene Ontology Kyoto Encyclopedia Genes Genomes. Results: In total, 1403 241 potential for drugs diseases, respectively, 81 intersecting yielded. included TNF, IL-6, IL-1β, pathways PI3K-Akt. treatment group exhibited effectively improved general signs, enhanced anti-inflammatory ability in vitro, reduced serum tissue expressions TNF- α, IL-1β inflammatory factors, decreased blood LPS levels Myd88, TLR4, PI3K, Akt, NF-κB p65 protein expression tissues. Conclusion: could inhibit production, which regulated TLR4/PI3K/Akt/NF-κB signaling pathway suppress related factors (i.e., TNF-α, IL-1β), thereby alleviating CP process.

Language: Английский

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