Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19.
COVID-19
alternative pathway
biomarkers
complement
Journal
Immunology
ISSN: 1365-2567
Titre abrégé: Immunology
Pays: England
ID NLM: 0374672
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
27
06
2022
accepted:
23
09
2022
pubmed:
30
9
2022
medline:
25
2
2023
entrez:
29
9
2022
Statut:
ppublish
Résumé
Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID-19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID-19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.
Identifiants
pubmed: 36175370
doi: 10.1111/imm.13585
pmc: PMC9537932
doi:
Substances chimiques
Complement System Proteins
9007-36-7
Complement C3b
80295-43-8
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
473-492Subventions
Organisme : Medical Research Council
ID : MC_PC_19059
Pays : United Kingdom
Organisme : Department of Health
ID : CO-CIN-01
Pays : United Kingdom
Organisme : Department of Health
ID : 200907
Pays : United Kingdom
Informations de copyright
© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.
Références
Risitano AM, Mastellos DC, Huber-Lang M, Yancopoulou D, Garlanda C, Ciceri F, et al. Complement as a target in COVID-19? Nat Rev Immunol. 2020;20(6):343-4. https://doi.org/10.1038/s41577-020-0320-7
Java A, Apicelli AJ, Liszewski MK, Coler-Reilly A, Atkinson JP, Kim AH, et al. The complement system in COVID-19: friend and foe? JCI Insight. 2020;5(15):e140711. https://doi.org/10.1172/jci.insight.140711
Noris M, Benigni A, Remuzzi G. The case of complement activation in COVID-19 multiorgan impact. Kidney Int. 2020;98(2):314-22. https://doi.org/10.1016/j.kint.2020.05.013
Afzali B, Noris M, Lambrecht BN, Kemper C. The state of complement in COVID-19. Nat Rev Immunol. 2022;22:77-84. https://doi.org/10.1038/s41577-021-00665-1
Ghebrehiwet B, Peerschke EI. Complement and coagulation: key triggers of COVID-19-induced multiorgan pathology. J Clin Invest. 2020;130(11):5674-6. https://doi.org/10.1172/JCI142780
Fletcher-Sandersjöö A, Bellander BM. Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review. Thromb Res. 2020;194:36-41. https://doi.org/10.1016/j.thromres.2020.06.027
Chauhan AJ, Wiffen LJ, Brown TP. COVID-19: a collision of complement, coagulation and inflammatory pathways. J Thromb Haemost. 2020;18(9):2110-7. https://doi.org/10.1111/jth.14981
Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol. 2021;17(1):46-64. https://doi.org/10.1038/s41581-020-00357-4
Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, et al. Complement activation and endothelial perturbation parallel COVID-19 severity and activity. J Autoimmun. 2021;116:102560. https://doi.org/10.1016/j.jaut.2020.102560
Hughes J, Nangaku M, Alpers CE, Shankland SJ, Couser WG, Johnson RJ. C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis. Am J Physiol Renal Physiol. 2000;278(5):F747-57. https://doi.org/10.1152/ajprenal.2000.278.5.F747
Xie CB, Jane-Wit D, Pober JS. Complement membrane attack complex: new roles, mechanisms of action, and therapeutic targets. Am J Pathol. 2020;190(6):1138-50. https://doi.org/10.1016/j.ajpath.2020.02.006
Lupu F, Keshari RS, Lambris JD, Coggeshall KM. Crosstalk between the coagulation and complement systems in sepsis. Thromb Res. 2014;133(Suppl 1(01)):S28-31. https://doi.org/10.1016/j.thromres.2014.03.014
Kenawy HI, Boral I, Bevington A. Complement-coagulation cross-talk: a potential mediator of the physiological activation of complement by low pH. Front Immunol. 2015;6(6):215. https://doi.org/10.3389/fimmu.2015.00215
Zelek WM, Cole J, Ponsford MJ, Harrison RA, Schroeder BE, Webb N, et al. Complement inhibition with the C5 blocker LFG316 in severe COVID-19. Am J Respir Crit Care Med. 2020;202(9):1304-8. https://doi.org/10.1164/rccm.202007-2778LE
Holter JC, Pischke SE, de Boer E, Lind A, Jenum S, Holten AR, et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A. 2020;117(40):25018-25. https://doi.org/10.1073/pnas.2010540117
de Nooijer AH, Grondman I, Janssen NAF, Netea MG, Willems L, van de Veerdonk FL, et al. RCI-COVID-19 study group. Complement activation in the disease course of coronavirus disease 2019 and its effects on clinical outcomes. J Infect Dis. 2021;223(2):214-24. https://doi.org/10.1093/infdis/jiaa646
Ma L, Sahu SK, Cano M, Kuppuswamy V, Bajwa J, McPhatter J, et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. 2021;6(59):eabh2259. https://doi.org/10.1126/sciimmunol.abh2259
Henry BM, Szergyuk I, de Oliveira MHS, Lippi G, Benoit JL, Vikse J, et al. Complement levels at admission as a reflection of coronavirus disease 2019 (COVID-19) severity state. J Med Virol. 2021;93(9):5515-22. https://doi.org/10.1002/jmv.27077
Pfister F, Vonbrunn E, Ries T, Jäck HM, Überla K, Lochnit G, et al. Complement activation in kidneys of patients with COVID-19. Front Immunol. 2021;11:594849. https://doi.org/10.3389/fimmu.2020.594849
Niederreiter J, Eck C, Ries T, Hartmann A, Märkl B, Büttner-Herold M, et al. Complement activation via the lectin and alternative pathway in patients with severe COVID-19. Front Immunol. 2022;13:835156. https://doi.org/10.3389/fimmu.2022.835156
Diurno F, Numis FG, Porta G, Cirillo F, Maddaluno S, Ragozzino A, et al. Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci. 2020;24:4040-7.
Mastaglio S, Ruggeri A, Risitano AM, Angelillo P, Yancopoulou D, Mastellos DC, et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin Immunol. 2020;215:108450.
Boussier J, Yatim N, Marchal A, Hadjadj J, Charbit B, El Sissy C, et al. Severe COVID-19 is associated with hyperactivation of the alternative complement pathway. J Allergy Clin Immunol. 2022;149(2):550-556.e2. https://doi.org/10.1016/j.jaci.2021.11.004
Alosaimi B, Mubarak A, Hamed ME, Almutairi AZ, Alrashed AA, AlJuryyan A, et al. Complement anaphylatoxins and inflammatory cytokines as prognostic markers for COVID-19 severity and in-hospital mortality. Front Immunol. 2021;12:668725. https://doi.org/10.3389/fimmu.2021.668725
Leatherdale A, Stukas S, Lei V, West HE, Campbell CJ, Hoiland RL, et al. Persistently elevated complement alternative pathway biomarkers in COVID-19 correlate with hypoxemia and predict in-hospital mortality. Med Microbiol Immunol. 2022;211:1-12. https://doi.org/10.1007/s00430-021-00725-2
Annane D, Heming N, Grimaldi-Bensouda L, Frémeaux-Bacchi V, Vigan M, Roux AL, et al. Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: a proof-of-concept study. EClinicalMedicine. 2020;28:100590. https://doi.org/10.1016/j.eclinm.2020.100590
Mastellos DC, da Silva BGP P, BAL F, Fonseca NP, Auxiliadora-Martins M, Mastaglio S, et al. Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clin Immunol. 2020;220:108598. https://doi.org/10.1016/j.clim.2020.108598. Epub 2020 Sep 19. PMID: 32961333.
Smith K, Pace A, Ortiz S, Kazani S, Rottinghaus S. A phase 3 open-label, randomized, controlled study to evaluate the efficacy and safety of intravenously administered Ravulizumab compared with best supportive care in patients with COVID-19 severe pneumonia, acute lung injury, or acute respiratory distress syndrome: a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):639. https://doi.org/10.1186/s13063-020-04548-z
Vlaar APJ, de Bruin S, Busch M, Timmermans SAMEG, van Zeggeren IE, Koning R, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020;2(12):e764-73. https://doi.org/10.1016/S2665-9913(20)30341-6
Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021 Mar 10;6(57):eabg9873. https://doi.org/10.1126/sciimmunol.abg9873
Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study. BMJ. 2020 May;22(369):m1985. https://doi.org/10.1136/bmj.m1985
Ali YM, Ferrari M, Lynch NJ, Yaseen S, Dudler T, Gragerov S, et al. Lectin pathway mediates complement activation by SARS-CoV-2 proteins. Front Immunol. 2021;12:714511. https://doi.org/10.3389/fimmu.2021.714511
Kim DM, Kim Y, Seo JW, Lee J, Park U, Ha NY, et al. Enhanced eosinophil-mediated inflammation associated with antibody and complement-dependent pneumonic insults in critical COVID-19. Cell Rep. 2021;37(1):109798. https://doi.org/10.1016/j.celrep.2021.109798. Epub 2021 Sep 20. PMID: 34587481; PMCID: PMC8450316.
Jarlhelt I, Nielsen SK, Jahn CXH, Hansen CB, Pérez-Alós L, Rosbjerg A, et al. SARS-CoV-2 antibodies mediate complement and cellular driven inflammation. Front Immunol. 2021;12:767981. https://doi.org/10.3389/fimmu.2021.767981. PMID: 34804055; PMCID: PMC8596567.
Harrison RA. The properdin pathway: an ‘alternative activation pathway’ or a ‘critical amplification loop’ for C3 and C5 activation? Semin Immunopathol. 2018;40(1):15-35. https://doi.org/10.1007/s00281-017-0661-x
Zipfel PF, Heinen S, Józsi M, Skerka C. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol. 2006;43(1-2):97-106. https://doi.org/10.1016/j.molimm.2005.06.015
Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood. 2020;136(18):2080-9. https://doi.org/10.1182/blood.2020008248
Lesher AM, Nilsson B, Song WC. Properdin in complement activation and tissue injury. Mol Immunol. 2013;56(3):191-8. https://doi.org/10.1016/j.molimm.2013.06.002
Chen JY, Cortes C, Ferreira VP. Properdin: a multifaceted molecule involved in inflammation and diseases. Mol Immunol. 2018;102:58-72. https://doi.org/10.1016/j.molimm.2018.05.018
Silkensen JR, Schwochau GB, Rosenberg ME. The role of clusterin in tissue injury. Biochem Cell Biol. 1994;72(11-12):483-8. https://doi.org/10.1139/o94-065
Garcia-Obregon S, Azkargorta M, Seijas I, Pilar-Orive J, Borrego F, Elortza F, et al. Identification of a panel of serum protein markers in early stage of sepsis and its validation in a cohort of patients. J Microbiol Immunol Infect. 2018;51(4):465-72. https://doi.org/10.1016/j.jmii.2016.12.002
Georg P, Astaburuaga-García R, Bonaguro L, Brumhard S, Michalick L, Lippert LJ, et al. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell. 2022;185(3):493-512.e25. https://doi.org/10.1016/j.cell.2021.12.040
Skendros P, Mitsios A, Chrysanthopoulou A, Mastellos DC, Metallidis S, Rafailidis P, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest. 2020;130(11):6151-7. https://doi.org/10.1172/JCI141374
A Study of the C3 Inhibitor AMY-101 in Patients with ARDS Due to COVID-19 (SAVE) [(accessed on 16th February 2022)]; Available online: https://clinicaltrials.gov/ct2/show/NCT04395456.
A Study of APL-9 in Adults with Mild to Moderate ARDS Due to COVID-19. [(accessed on 16th February 2022)]; Available online: https://clinicaltrials.gov/ct2/show/NCT04402060.
Risitano AM, Kulasekararaj AG, Lee JW, Maciejewski JP, Notaro R, Brodsky R, et al. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021;106(12):3188-97. https://doi.org/10.3324/haematol.2020.261826
Risitano AM, Röth A, Soret J, Frieri C, de Fontbrune FS, Marano L, et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021;8(5):e344-54. https://doi.org/10.1016/S2352-3026(21)00028-4
Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591(7848):92-8. https://doi.org/10.1038/s41586-020-03065-y
Marshall JC, Murthy S, Diaz J, Adhikari NK, Angus DC, Arabi YM, et al. WHO working group on the clinical characterisation and management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20(8):e192-7. https://doi.org/10.1016/S1473-3099(20)30483-7
ISARIC clinical characterisation group. Global outbreak research: harmony not hegemony. Lancet Infect Dis. 2020;20(7):770-2. https://doi.org/10.1016/S1473-3099(20)30440-0
Hanneman SK, Cox CD, Green KE, Kang DH. Estimating intra- and inter-assay variability in salivary cortisol. Biol Res Nurs. 2011;13(3):243-50. https://doi.org/10.1177/1099800411404061
Haddock E, Feldmann F, Shupert WL, Feldmann H. Inactivation of SARS-CoV-2 laboratory specimens. Am J Trop Med Hyg. 2021;104(6):2195-8. https://doi.org/10.4269/ajtmh.21-0229
Livigni A, O'Hara L, Polak ME, Angus T, Wright DW, Smith LB, et al. A graphical and computational modeling platform for biological pathways. Nat Protoc. 2018;13(4):705-22. https://doi.org/10.1038/nprot.2017.144