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

Med, Год журнала: 2024, Номер 5(3), С. 239 - 253.e5

Опубликована: Фев. 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.

Язык: Английский

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Complement activation in COVID-19 and targeted therapeutic options: A scoping review

Blood Reviews, Год журнала: 2022, Номер 57, С. 100995 - 100995

Опубликована: Июль 31, 2022

Increasing evidence suggests that activation of the complement system plays a key role in pathogenesis and disease severity Coronavirus 2019 (COVID-19). We used systematic approach to create an overview COVID-19 based on histopathological, preclinical, multiomics, observational clinical interventional studies. A total 1801 articles from PubMed, EMBASE Cochrane was screened which 157 were included this scoping review. Histopathological, multiomics studies showed apparent through all three pathways correlation with mortality. The targeted at different levels COVID-19, C5 C5a inhibition seem most promising. Adequately powered, double blind RCTs are necessary order further investigate effect targeting COVID-19.

Язык: 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, Год журнала: 2023, Номер 228(3), С. 152393 - 152393

Опубликована: Май 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

Язык: Английский

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Complement‐driven hemolytic uremic syndrome

American Journal of Hematology, Год журнала: 2023, Номер 98(S4)

Опубликована: Янв. 23, 2023

Overactivation of the complement alternative pathway drives pathogenesis primary atypical hemolytic uremic syndrome (aHUS). Genetically-determined or acquired dysregulation is frequently identified in patients with aHUS, pregnancy-related (HUS), and severe hypertension-associated HUS. In contrast, it still unclear whether self-limited activation, which occurs other forms HUS, provides key mechanistic clues results from endothelial damage. Development novel biomarkers underway to firmly establish complement-driven pathogenesis. C5 blockade therapy has revolutionized management aHUS patients, resulting a halving subpopulation under chronic dialysis over course few years. On hand, efficacy secondary as assessed by small uncontrolled case series, less compelling should be investigated through properly designed prospective clinical trials. The increased risk meningococcal infection, related inhibition, must rigorously addressed suitable prophylaxis. Treatment duration determined based on an individualized benefit/risk assessment.

Язык: Английский

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Alternative Complement Pathway in Carotid Atherosclerosis: Low Plasma Properdin Levels Associate With Long‐Term Cardiovascular Mortality

Journal of the American Heart Association, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Background Complement activation may promote atherosclerosis. Yet, data on the to which extent complement, and more specifically alternative complement pathway, is activated in patients with carotid atherosclerosis related adverse outcome these patients, are scarce. Methods Results We measured, by ELISA, plasma levels of factor D, properdin, C3bBbP (C3 convertase), H advanced a Discovery (n=324) Validation (n=206) cohort relation (mean follow‐up 7.8 6.6 years, respectively). Our major findings were as follows. Compared healthy controls, had increased ( P <0.001), but not H, an inhibitor compared controls. Although elevated properdin within low (ie, <median patient group) significantly associated cardiovascular mortality. This was seen both (HR 2.31, =0.019) (hazard ratio [HR], 2.81, =0.014). In contrast circulating levels, high intraplaque (assessed ELISA) correlated markers plaque vulnerability symptomatology. Conclusions show strong independent association mortality 2 cohorts. Conversely, linked features vulnerability, potentially reflecting deposition at site inflammation or local production atherosclerotic lesion indicating enhanced pathway activation.

Язык: Английский

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IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 9, 2024

Abstract The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the IgM N-glycosylation has not been studied viral infection. analysis from healthy controls hospitalized disease 2019 (COVID-19) patients reveals increased high-mannose sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, degree total mannosylation correlate significantly markers We link changes expression Golgi glycosyltransferases. Lastly, we observe antigen-specific antibody-dependent complement deposition is elevated in modulated by exoglycosidase digestion. Taken together, this work links severity highlights need to understand downstream function disease.

Язык: Английский

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Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID‐19

Immunology, Год журнала: 2022, Номер 168(3), С. 473 - 492

Опубликована: Сен. 30, 2022

Complement, a critical defence against pathogens, has been implicated as driver of pathology in COVID-19. Complement activation products are detected plasma and tissues complement blockade is considered for therapy. To delineate roles immunopathogenesis, we undertook the largest comprehensive study COVID-19 to date, profiling 16 biomarkers, including key components, regulators products, 966 samples from 682 hospitalized patients collected across hospitalization period part UK ISARIC4C (International Acute Respiratory Emerging Infection Consortium) study. Unsupervised clustering biomarkers mapped disease severity supervised machine learning identified marker sets early that predicted peak severity. Compared healthy controls, proteins (Ba, iC3b, terminal complex) were significantly altered admission all groups. Elevated alternative pathway markers (Ba iC3b) decreased regulator (properdin) associated with more severe risk death. Levels most reduced disease, consistent consumption tissue deposition. Latent class mixed modelling cumulative incidence analysis trajectory increase Ba be strong predictor The data demonstrate early-onset, uncontrolled complement, driven by sustained progressive amplification through loop ubiquitous feature COVID-19, further exacerbated disease. These findings provide novel insights into immunopathogenesis inform strategies therapeutic intervention.

Язык: Английский

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Mechanisms of COVID-19 Associated Pulmonary Thrombosis: A Narrative Review

Biomedicines, Год журнала: 2023, Номер 11(3), С. 929 - 929

Опубликована: Март 16, 2023

COVID-19, the infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is frequently associated with pulmonary thrombotic events, especially in hospitalized patients. Severe SARS-CoV-2 infection characterized a proinflammatory state and an disbalance hemostasis. Immune pathology analysis supports inflammatory nature of arterial thrombi composed white blood cells, neutrophils, CD3+ CD20+ lymphocytes, fibrin, red platelets. cytokines, chemokines, complement system are key drivers immunothrombosis, as they induce damage endothelial cells initiate procoagulant positive feedback loops. Neutrophil extracellular traps induced COVID-19-associated “cytokine storm”, platelets, coagulation pathways close inflammation–endotheliopathy–thrombosis axis, contributing to SARS-CoV-2-associated events. The hypothesis immunothrombosis also supported minor role venous thromboembolism chest CT imaging data showing peripheral clots lesions high incidence events despite routine thromboprophylaxis. Understanding complex mechanisms behind COVID-19-induced thrombosis will lead future combination therapies for patients that would target crossroads pathways.

Язык: Английский

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

European Journal of Immunology, Год журнала: 2024, Номер 54(11)

Опубликована: Авг. 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.

Язык: Английский

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A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

Science Translational Medicine, Год журнала: 2023, Номер 15(710)

Опубликована: Авг. 23, 2023

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of mechanisms driving disease pathology. The complement system is not only a crucial component innate host defense but can also contribute to tissue injury. Although all pathways have been implicated pathogenesis, upstream drivers and downstream effects on injury remain poorly defined. We demonstrate that activation primarily mediated by alternative pathway, we provide comprehensive atlas alterations around time respiratory deterioration. Proteomic single-cell sequencing mapping across cell types tissues reveals division labor between lung epithelial, stromal, myeloid cells production, addition liver-derived factors. identify IL-6 STAT1/3 signaling as an driver responses, linking dysregulation approved therapies. Furthermore, exploratory proteomic study indicates inhibition C5 decreases epithelial damage markers severity. Collectively, these results support key druggable feature COVID-19.

Язык: Английский

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