Vai trò mới nổi của hệ thống bổ thể trong COVID-19 và các bệnh virus hô hấp khác

Cellular and Molecular Life Sciences - Tập 81 - Trang 1-18 - 2024
Mark T. Xiao1,2, Calder R. Ellsworth1,2, Xuebin Qin1,2
1Division of Comparative Pathology, Tulane National Primate Research Center, Health Sciences Campus, Covington, USA
2Department of Microbiology and Immunology, Tulane University, School of Medicine, New Orleans, USA

Tóm tắt

Hệ thống bổ thể, một thành phần quan trọng của miễn dịch bẩm sinh, cung cấp hàng rào đầu tiên chống lại nhiễm trùng vi khuẩn; tuy nhiên, đại dịch COVID-19 đã tiết lộ rằng nó cũng có thể gây ra những biến chứng nghiêm trọng trong bối cảnh bệnh lý hô hấp do virus. Trong bài viết này, chúng tôi xem xét các cơ chế kích hoạt và điều hòa hệ thống bổ thể và khám phá vai trò của chúng trong việc bảo vệ chống lại nhiễm trùng cũng như làm trầm trọng thêm tình trạng bệnh. Chúng tôi thảo luận về các bằng chứng mới nổi liên quan đến liệu pháp nhắm mục tiêu vào hệ thống bổ thể trong COVID-19 và so sánh vai trò của hệ thống bổ thể trong các bệnh virus hô hấp khác như cúm và virus hợp bào hô hấp. Chúng tôi xem xét các nghiên cứu cơ chế gần đây và các mô hình động vật có thể được sử dụng cho các cuộc điều tra thêm. Các nghiên cứu knockout mới được đề xuất để hiểu rõ hơn về các sắc thái của việc kích hoạt hệ thống bổ thể trong các bệnh virus hô hấp.

Từ khóa

#hệ thống bổ thể #miễn dịch bẩm sinh #COVID-19 #bệnh virus hô hấp #liệu pháp nhắm mục tiêu #cúm #virus hợp bào hô hấp

Tài liệu tham khảo

Liu F, Dai S, Gordon J, Qin X (2014) Complement and HIV-I infection/HIV-associated neurocognitive disorders. J Neurovirol 20(2):184–198. https://doi.org/10.1007/s13365-014-0243-9 Acosta J, Qin X, Halperin J (2004) Complement and complement regulatory proteins as potential molecular targets for vascular diseases. Curr Pharm Des 10(2):203–211. https://doi.org/10.2174/1381612043453441 Ehrnthaller C, Ignatius A, Gebhard F, Huber-Lang M (2011) New insights of an old defense system: structure, function, and clinical relevance of the complement system. Mol Med 17(3):317–329. https://doi.org/10.2119/molmed.2010.00149 Garred P, Tenner AJ, Mollnes TE (2021) Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev 73(2):792–827. https://doi.org/10.1124/pharmrev.120.000072 Heesterbeek DAC, Angelier ML, Harrison RA, Rooijakkers SHM (2018) Complement and bacterial infections: from molecular mechanisms to therapeutic applications. J Innate Immun 10(5–6):455–464. https://doi.org/10.1159/000491439 Bera MM, Lu B, Martin TR et al (2011) Th17 cytokines are critical for respiratory syncytial virus-associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. J Immunol 187(8):4245–4255. https://doi.org/10.4049/jimmunol.1101789 Datta PK, Liu F, Fischer T, Rappaport J, Qin X (2020) SARS-CoV-2 pandemic and research gaps: understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy. Theranostics 10(16):7448–7464. https://doi.org/10.7150/thno.48076 Kopf M, Abel B, Gallimore A, Carroll M, Bachmann MF (2002) Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat Med 8(4):373–378 Rattan A, Pawar SD, Nawadkar R et al (2017) Synergy between the classical and alternative pathways of complement is essential for conferring effective protection against the pandemic influenza A(H1N1) 2009 virus infection. PLoS Pathog 13(3):e1006248. https://doi.org/10.1371/journal.ppat.1006248 Nonaka M, Kimura A (2006) Genomic view of the evolution of the complement system. Immunogenetics 58(9):701–713. https://doi.org/10.1007/s00251-006-0142-1 Sarma JV, Ward PA (2011) The complement system. Cell Tissue Res 343(1):227–235. https://doi.org/10.1007/s00441-010-1034-0 Zhou X, Hu W, Qin X (2008) The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy. Oncologist 13(9):954–966 Morgan BP (1999) Regulation of the complement membrane attack pathway. Crit Rev Immunol 19(3):173–198 Cooper NR (1985) The classical complement pathway: activation and regulation of the first complement component. Adv Immunol 37:151–216. https://doi.org/10.1016/s0065-2776(08)60340-5 Dangl JL, Wensel TG, Morrison SL, Stryer L, Herzenberg LA, Oi VT (1988) Segmental flexibility and complement fixation of genetically engineered chimeric human, rabbit and mouse antibodies. EMBO J 7(7):1989–1994. https://doi.org/10.1002/j.1460-2075.1988.tb03037.x Isenman DE, Dorrington KJ, Painter RH (1975) The structure and function of immunoglobulin domains. II. The importance of interchain disulfide bonds and the possible role of molecular flexibility in the interaction between immunoglobulin G and complement. J Immunol 114(6):1726–1729 Beltrame MH, Catarino SJ, Goeldner I, Boldt AB, de Messias-Reason IJ (2014) The lectin pathway of complement and rheumatic heart disease. Front Pediatr 2:148. https://doi.org/10.3389/fped.2014.00148 Qin X, Gao B (2006) The complement system in liver diseases. Cell Mol Immunol 3(5):333–340 Morgan BP, Harris CL (1999) Complement regulatory proteins. Academic Press, London Walport MJ (2001) Complement. First of two parts. N Engl J Med 344(14):1058–1066 Walport MJ (2001) Complement. Second of two parts. N Engl J Med 344(15):1140–1144 Carney DF, Lang TJ, Shin ML (1990) Multiple signal messengers generated by terminal complement complexes and their role in terminal complexes elimination. J Immunol 145:621–629 Papadimitriou JC, Ramm LE, Drachenberg CB, Trump BF, Shin ML (1991) Quantitative analysis of adenine nucleotides during the prelytic phase of cell death mediated by C5b-9. J Immunol 147(1):212–217 Niculescu F, Rus H, van Biesen T, Shin ML (1997) Activation of Ras and mitogen-activated protein kinase pathway by terminal complement complexes is G protein dependent. J Immunol 158(9):4405–4412 Niculescu F, Rus H (1999) Complement activation and atherosclerosis. Mol Immunol Sep-Oct 36(13–14):949–955 Niculescu F, Badea T, Rus H (1999) Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. Atherosclerosis 142(1):47–56 Niculescu F, Rus H (2004) The role of complement activation in atherosclerosis. Immunol Res 30(1):73–80 Hila S, Soane L, Koski CL (2001) Sublytic C5b–9-stimulated Schwann cell survival through PI 3-kinase-mediated phosphorylation of BAD. Glia 36(1):58–67 Soane L, Cho HJ, Niculescu F, Rus H, Shin ML (2001) C5b-9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3-kinase/Akt pathway. J Immunol 167(4):2305–2311 Fosbrink M, Niculescu F, Rus V, Shin ML, Rus H (2006) C5b–9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J Biol Chem 281(28):19009–19018 Benzaquen LR, Nicholson-Weller A, Halperin JA (1994) Terminal complement proteins C5b–9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med 179(3):985–992 Nicholson-Weller A, Halperin JA (1993) Membrane signaling by complement C5b–9, the membrane attack complex. Immunol Res 12(3):244–257 Wu G, Chen T, Shahsafaei A et al (2010) Complement regulator CD59 protects against angiotensin II-induced abdominal aortic aneurysms in mice. Circulation 121(11):1338–1346 Wu G, Hu W, Shahsafaei A et al (2009) Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res 104(4):550–558. https://doi.org/10.1161/CIRCRESAHA.108.191361 Liszewski MK, Kolev M, Le Friec G et al (2013) Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39(6):1143–1157. https://doi.org/10.1016/j.immuni.2013.10.018 Arbore G, Kemper C, Kolev M (2017) Intracellular complement—the complosome—in immune cell regulation. Mol Immunol 89:2–9. https://doi.org/10.1016/j.molimm.2017.05.012 Reichhardt MP, Meri S (2018) Intracellular complement activation—An alarm raising mechanism? Semin Immunol 38:54–62. https://doi.org/10.1016/j.smim.2018.03.003 Ferreira VP, Pangburn MK, Cortés C (2010) Complement control protein factor H: the good, the bad, and the inadequate. Mol Immunol 47(13):2187–2197. https://doi.org/10.1016/j.molimm.2010.05.007 Risitano AM (2013) Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv Exp Med Biol 735:155–172. https://doi.org/10.1007/978-1-4614-4118-2_10 Joseph C, Gattineni J (2013) Complement disorders and hemolytic uremic syndrome. Curr Opin Pediatr 25(2):209–215. https://doi.org/10.1097/MOP.0b013e32835df48a Lynch PJ (2006) Lungs-simple diagram of lungs and trachea. Wikipedia Lynch PJ (2021) Heart anterior exterior view. Wikipedia Cole M Image of Liver. Vecteezy.com National Center for PTSD USDoV (2021) SARS-CoV-2 particle diagram. brainline2021 TefiM (2017) Healthy human elastic artery, detailed illustration Hu W, Ge X, You T et al (2011) Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis. Cancer Res 71(6):2298–2307. https://doi.org/10.1158/0008-5472.CAN-10-3016 Zhang R, Liu Q, Liao Q, Zhao Y (2018) CD59: a promising target for tumor immunotherapy. Future Oncol 14(8):781–791. https://doi.org/10.2217/fon-2017-0498 Saifuddin M, Parker CJ, Peeples ME et al (1995) Role of virion-associated glycosylphosphatidylinositol-linked proteins CD55 and CD59 in complement resistance of cell line-derived and primary isolates of HIV-1. J Exp Med 182(2):501–509. https://doi.org/10.1084/jem.182.2.501 Nguyen DH, Hildreth JE (2000) Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts. J Virol 74(7):3264–3272 Stoiber H, Pruenster M, Ammann CG, Dierich MP (2005) Complement-opsonized HIV: the free rider on its way to infection. Mol Immunol 42(2):153–160 Rautemaa R, Helander T, Meri S (2002) Herpes simplex virus 1 infected neuronal and skin cells differ in their susceptibility to complement attack. Immunology 106(3):404–411 Bernet J, Mullick J, Singh AK, Sahu A (2003) Viral mimicry of the complement system. J Biosci 28(3):249–264 Yu Q, Yu R, Qin X (2010) The good and evil of complement activation in HIV-1 infection. Cell Mol Immunol 7:334–340 Java A, Apicelli AJ, Liszewski MK et al (2020) The complement system in COVID-19: friend and foe? JCI Insight. https://doi.org/10.1172/jci.insight.140711 Que Y, Hu C, Wan K et al (2022) Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality. Int Rev Immunol 41(2):217–230. https://doi.org/10.1080/08830185.2021.1884248 Skendros P, Mitsios A, Chrysanthopoulou A et al (2020) Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest 130(11):6151–6157. https://doi.org/10.1172/jci141374 Sinkovits G, Mező B, Réti M et al (2021) Complement overactivation and consumption predicts in-hospital mortality in SARS-CoV-2 infection. Front Immunol 12:663187. https://doi.org/10.3389/fimmu.2021.663187 Rambaldi A, Gritti G, Micò MC et al (2020) Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab. Immunobiology 225(6):152001. https://doi.org/10.1016/j.imbio.2020.152001 Ma L, Sahu SK, Cano M et al (2021) Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. https://doi.org/10.1126/sciimmunol.abh2259 Devalaraja-Narashimha K, Ehmann PJ, Huang C et al (2023) Association of complement pathways with COVID-19 severity and outcomes. Microb Infect 25(4):105081. https://doi.org/10.1016/j.micinf.2022.105081 Holter JC, Pischke SE, de Boer E et al (2020) Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci 117(40):25018–25025. https://doi.org/10.1073/pnas.2010540117 Giavedoni P, Podlipnik S, Pericàs JM et al (2020) Skin manifestations in COVID-19: prevalence and relationship with disease severity. J Clin Med. https://doi.org/10.3390/jcm9103261 Carvelli J, Demaria O, Vély F et al (2020) Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature 588(7836):146–150. https://doi.org/10.1038/s41586-020-2600-6 Macor P, Durigutto P, Mangogna A et al (2021) Multiple-organ complement deposition on vascular endothelium in COVID-19 patients. Biomedicines. https://doi.org/10.3390/biomedicines9081003 Robbins RA, Russ WD, Rasmussen JK, Clayton MM (1987) Activation of the complement system in the adult respiratory distress syndrome. Am Rev Respir Dis 135(3):651–658. https://doi.org/10.1164/arrd.1987.135.3.651 Zilow G, Joka T, Obertacke U, Rother U, Kirschfink M (1992) Generation of anaphylatoxin C3a in plasma and bronchoalveolar lavage fluid in trauma patients at risk for the adult respiratory distress syndrome. Crit Care Med 20(4):468–473. https://doi.org/10.1097/00003246-199204000-00006 Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS (1980) Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value. Lancet 1(8175):947–949. https://doi.org/10.1016/s0140-6736(80)91403-8 Peffault de Latour R, Bergeron A, Lengline E et al (2020) Complement C5 inhibition in patients with COVID-19—a promising target? Haematologica 105(12):2847–2850. https://doi.org/10.3324/haematol.2020.260117 Rajamanickam A, Nathella PK, Venkataraman A et al (2023) Levels of complement components in children with acute COVID-19 or multisystem inflammatory syndrome. JAMA Netw Open 6(3):e231713–e231713. https://doi.org/10.1001/jamanetworkopen.2023.1713 Savitt AG, Manimala S, White T et al (2021) SARS-CoV-2 exacerbates COVID-19 pathology through activation of the complement and kinin systems. Front Immunol 12:767347. https://doi.org/10.3389/fimmu.2021.767347 Afzali B, Noris M, Lambrecht BN, Kemper C (2022) The state of complement in COVID-19. Nat Revi Immunol 22(2):77–84. https://doi.org/10.1038/s41577-021-00665-1 Legrand M, Bell S, Forni L et al (2021) Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol 17(11):751–764. https://doi.org/10.1038/s41581-021-00452-0 Pfister F, Vonbrunn E, Ries T et al (2020) Complement activation in kidneys of patients with COVID-19. Front Immunol 11:594849. https://doi.org/10.3389/fimmu.2020.594849 Santana MF, Guerra MT, Hundt MA et al (2022) Correlation between clinical and pathological findings of liver injury in 27 patients with lethal COVID-19 infections in Brazil. Hepatol Commun 6(2):270–280. https://doi.org/10.1002/hep4.1820 Pellegrini D, Kawakami R, Guagliumi G et al (2021) Microthrombi as a major cause of cardiac injury in COVID-19. Circulation 143(10):1031–1042. https://doi.org/10.1161/CIRCULATIONAHA.120.051828 Magro CM, Mulvey JJ, Laurence J et al (2021) The differing pathophysiologies that underlie COVID-19-associated perniosis and thrombotic retiform purpura: a case series. Br J Dermatol 184(1):141–150. https://doi.org/10.1111/bjd.19415 Ville S, Le Bot S, Chapelet-Debout A et al (2021) Atypical HUS relapse triggered by COVID-19. Kidney Int 99(1):267–268. https://doi.org/10.1016/j.kint.2020.10.030 Kaufeld J, Reinhardt M, Schröder C et al (2021) Atypical hemolytic and uremic syndrome triggered by infection with SARS-CoV2. Kidney Int Rep 6(10):2709–2712. https://doi.org/10.1016/j.ekir.2021.07.004 Otieno SB, Altahan A, Kaweeta F, Karri S, Alnoor F, Johnson R (2021) Severe hemolysis in a COVID-19 patient with paroxysmal nocturnal hemoglobinuria. Case Rep Hematol. https://doi.org/10.1155/2021/6619177 Hines A, Hakim N, Barrientos J (2021) COVID-19 infection presenting as paroxysmal nocturnal hemoglobinuria. Clin Case Rep 9(8):e04636. https://doi.org/10.1002/ccr3.4636 Uwatoko R, Shindo M, Hashimoto N et al (2023) Relapse of atypical hemolytic uremic syndrome triggered by COVID-19: a lesson for the clinical nephrologist. J Nephrol. https://doi.org/10.1007/s40620-023-01595-y Sinkovits G, Schnur J, Hurler L et al (2022) Evidence, detailed characterization and clinical context of complement activation in acute multisystem inflammatory syndrome in children. Sci Rep 12(1):19759. https://doi.org/10.1038/s41598-022-23806-5 Ziegler CGK, Allon SJ, Nyquist SK et al (2020) SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181(5):1016-1035 e19. https://doi.org/10.1016/j.cell.2020.04.035 Zhang H, Gerasimovskaya E, McCarthy MK et al (2023) Local complement contributes to pathogenic activation of lung endothelial cells in SARS-CoV-2 infection. Am J Respir Cell Mol Biol 69(2):210–219. https://doi.org/10.1165/rcmb.2022-0373OC Navratil JS, Watkins SC, Wisnieski JJ, Ahearn JM (2001) The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells. J Immunol 166(5):3231–3239 Albertí S, Marqués G, Camprubí S et al (1993) C1q binding and activation of the complement classical pathway by Klebsiella pneumoniae outer membrane proteins. Infect Immun 61(3):852–860. https://doi.org/10.1128/iai.61.3.852-860.1993 Beirag N, Varghese PM, Neto MM et al (2023) Complement activation-independent attenuation of SARS-CoV-2 infection by C1q and C4b-binding protein. Viruses. https://doi.org/10.3390/v15061269 Varghese PM, Kishore U, Rajkumari R (2022) Human C1q regulates influenza A virus infection and inflammatory response via its globular domain. Int J Mol Sci. https://doi.org/10.3390/ijms23063045 Hurler L, Szilágyi Á, Mescia F et al (2023) Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups Original Research. Front Immunol. https://doi.org/10.3389/fimmu.2023.1162171 Gao T, Zhu L, Liu H et al (2022) Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation. Signal Transduct Targeted Therapy 7(1):318. https://doi.org/10.1038/s41392-022-01133-5 Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA (2020) Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood 136(18):2080–2089. https://doi.org/10.1182/blood.2020008248 Ali YM, Carnell GW, Fumagalli S et al (2023) Inhibition of the lectin pathway of complement activation reduces acute respiratory distress syndrome severity in a mouse model of SARS-CoV-2 infection. J Infect Dis. https://doi.org/10.1093/infdis/jiad462 Queiroz MAF, Santiago AM, Brito W et al (2023) Polymorphisms in the MBL2 gene are associated with the plasma levels of MBL and the cytokines IL-6 and TNF-α in severe COVID-19. Front Immunol 14:1151058. https://doi.org/10.3389/fimmu.2023.1151058 Waters AM, Licht C (2011) aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol 26(1):41–57. https://doi.org/10.1007/s00467-010-1556-4 Siggins MK, Davies K, Fellows R et al (2023) Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19. Immunology 168(3):473–492. https://doi.org/10.1111/imm.13585 Tsiftsoglou SA, Gavriilaki E, Touloumenidou T et al (2023) Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection. Immunobiology 228(2):152351. https://doi.org/10.1016/j.imbio.2023.152351 Kawakami E, Saiki N, Yoneyama Y et al (2023) Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19. Cell Stem Cell 30(10):1315–1330. https://doi.org/10.1016/j.stem.2023.09.001 Kumar J, Dhyani S, Kumar P, Sharma NR, Ganguly S (2023) SARS-CoV-2-encoded ORF8 protein possesses complement inhibitory properties. J Biol Chem 299(3):102930. https://doi.org/10.1016/j.jbc.2023.102930 Sahu SK, Ozantürk AN, Kulkarni DH et al (2023) Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury. Sci Immunol 8(80):eabp9547. https://doi.org/10.1126/sciimmunol.abp9547 Wang S, Yao X, Ma S et al (2021) A single-cell transcriptomic landscape of the lungs of patients with COVID-19. Nat Cell Biol 23(12):1314–1328. https://doi.org/10.1038/s41556-021-00796-6 Chouaki Benmansour N, Carvelli J, Vivier E (2021) Complement cascade in severe forms of COVID-19: recent advances in therapy. Eur J Immunol 51(7):1652–1659. https://doi.org/10.1002/eji.202048959 Ruggenenti P, Di Marco F, Cortinovis M et al (2021) Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study. PLoS ONE 16(12):e0261113. https://doi.org/10.1371/journal.pone.0261113 Annane D, Heming N, Grimaldi-Bensouda L et al (2020) Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: a proof-of-concept study. eClinicalMedicine. https://doi.org/10.1016/j.eclinm.2020.100590 F. Diurno et al (2020) Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci 24(N. 7):4040–4047 Lim EHT, van Amstel RBE, de Boer VV et al (2023) Complement activation in COVID-19 and targeted therapeutic options: a scoping review. Blood Rev 57:100995. https://doi.org/10.1016/j.blre.2022.100995 Zelek WM, Cole J, Ponsford MJ et al (2020) Complement Inhibition with the C5 Blocker LFG316 in Severe COVID-19. Am J Respir Crit Care Med 202(9):1304–1308. https://doi.org/10.1164/rccm.202007-2778LE McEneny-King AC, Monteleone JPR, Kazani SD, Ortiz SR (2021) Pharmacokinetic and pharmacodynamic evaluation of ravulizumab in adults with severe coronavirus disease 2019. Infect Dis Ther 10(2):1045–1054. https://doi.org/10.1007/s40121-021-00425-7 Witzenrath M, Paassen P, Heunks L et al (2022) Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Respir Med. https://doi.org/10.1016/S2213-2600(22)00297-1 Skendros P, Germanidis G, Mastellos DC et al (2022) Complement C3 inhibition in severe COVID-19 using compstatin AMY-101. Sci Adv 8(33):eabo2341. https://doi.org/10.1126/sciadv.abo2341 Mastellos DC, Pires da Silva BGP, Fonseca BAL et al (2020) Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clin Immunol 220:108598. https://doi.org/10.1016/j.clim.2020.108598 Urwyler P, Moser S, Charitos P et al (2020) Treatment of COVID-19 with conestat alfa, a regulator of the complement, contact activation and Kallikrein–Kinin system. Front Immunol 11:2072. https://doi.org/10.3389/fimmu.2020.02072 Mansour E, Palma AC, Ulaf RG et al (2021) Safety and outcomes associated with the pharmacological inhibition of the Kinin–Kallikrein system in severe COVID-19. Viruses. https://doi.org/10.3390/v13020309 Zhou Y, Lu K, Pfefferle S et al (2010) A single asparagine-linked glycosylation site of the severe acute respiratory syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms. J Virol 84(17):8753–8764. https://doi.org/10.1128/jvi.00554-10 Hamed ME, Naeem A, Alkadi H et al (2021) Elevated expression levels of lung complement anaphylatoxin, neutrophil chemoattractant chemokine IL-8, and RANTES in MERS-CoV-infected patients: predictive biomarkers for disease severity and mortality. J Clin Immunol 41(7):1607–1620. https://doi.org/10.1007/s10875-021-01061-z Alsolamy S, Arabi YM (2015) Infection with Middle East respiratory syndrome coronavirus. Can J Respir Ther Fall 51(4):102 Pormohammad A, Ghorbani S, Khatami A et al (2020) Comparison of confirmed COVID-19 with SARS and MERS cases—Clinical characteristics, laboratory findings, radiographic signs and outcomes: a systematic review and meta-analysis. Rev Med Virol 30(4):e2112. https://doi.org/10.1002/rmv.2112 Raj VS, Mou H, Smits SL et al (2013) Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495(7440):251–254. https://doi.org/10.1038/nature12005 Saad M, Omrani AS, Baig K et al (2014) Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis 29:301–306. https://doi.org/10.1016/j.ijid.2014.09.003 Gralinski LE, Sheahan TP, Morrison TE et al (2018) Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. MBio. https://doi.org/10.1128/mBio.01753-18 Jiang Y, Zhao G, Song N et al (2018) Blockade of the C5a–C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerg Microbes Infect 7(1):77. https://doi.org/10.1038/s41426-018-0063-8 Becker K, Beythien G, de Buhr N et al (2021) Vasculitis and neutrophil extracellular traps in lungs of golden syrian hamsters with SARS-CoV-2. Front Immunol 12:640842. https://doi.org/10.3389/fimmu.2021.640842 Aid M, Vidal SJ, Piedra-Mora C et al (2022) Ad26.COV2.S prevents upregulation of SARS-CoV-2 induced pathways of inflammation and thrombosis in hamsters and rhesus macaques. PLoS Pathog 18(4):1009990. https://doi.org/10.1371/journal.ppat.1009990 Muñoz-Fontela C, Dowling WE, Funnell SGP et al (2020) Animal models for COVID-19. Nature 586(7830):509–515. https://doi.org/10.1038/s41586-020-2787-6 Zheng J, Wong LR, Li K et al (2021) COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature 589(7843):603–607. https://doi.org/10.1038/s41586-020-2943-z Oladunni FS, Park JG, Pino PA et al (2020) Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. Nat Commun 11(1):6122. https://doi.org/10.1038/s41467-020-19891-7 Qin Z, Liu F, Blair R et al (2021) Endothelial cell infection and dysfunction, immune activation in severe COVID-19. Theranostics 11(16):8076–8091. https://doi.org/10.7150/thno.61810 Khatun MS, Remcho TP, Qin X, Kolls JK (2023) Cell-intrinsic and -extrinsic effects of SARS-CoV-2 RNA on pathogenesis: single-cell meta-analysis. mSphere 8(5):e0037523. https://doi.org/10.1128/msphere.00375-23 Dong W, Mead H, Tian L et al (2022) The K18-human ACE2 transgenic mouse model recapitulates non-severe and severe COVID-19 in response to an infectious dose of the SARS-CoV-2 Virus. J Virol 96(1):e00964-e1021. https://doi.org/10.1128/JVI.00964-21 Dong W, Mead H, Tian L et al (2022) The K18-Human ACE2 transgenic mouse model recapitulates non-severe and severe COVID-19 in response to an infectious dose of the SARS-CoV-2 virus. J Virol 96(1):e0096421. https://doi.org/10.1128/jvi.00964-21 Leist SR, Dinnon KH 3rd, Schäfer A et al (2020) A mouse-adapted SARS-CoV-2 induces acute lung injury and mortality in standard laboratory mice. Cell 183(4):1070-1085.e12. https://doi.org/10.1016/j.cell.2020.09.050 Wong L-YR, Zheng J, Wilhelmsen K et al (2022) Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19. Nature 605(7908):146–151. https://doi.org/10.1038/s41586-022-04630-3 Spicer AP, Seldin MF, Gendler SJ (1995) Molecular cloning and chromosomal localization of the mouse decay- accelerating factor genes Duplicated genes encode glycosylphosphatidylinositol-anchored and transmembrane forms. J Immunol 155(6):3079–3091 Lin F, Fukuoka Y, Spicer A et al (2001) Tissue distribution of products of the mouse decay-accelerating factor (DAF) genes Exploitation of a Daf1 knock-out mouse and site-specific monoclonal antibodies. Immunology 104(2):215–225. https://doi.org/10.1046/j.1365-2567.2001.01287.x Powell MB, Marchbank KJ, Rushmere NK, van den Berg CW, Morgan BP (1997) Molecular cloning, chromosomal localization, expression, and functional characterization of the mouse analogue of human CD59. J Immunol 158:1692–1702 Qian YM, Qin X, Miwa T, Sun X, Halperin JA, Song WC (2000) Identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59. J Immunol 165(5):2528–2534 Paul MS, Aegerter M, Cepek K, Miller MD, Weis JH (1990) The murine complement receptor gene family. III. The genomic and transcriptional complexity of the Crry and Crry-ps genes. J Immunol 144(5):1988–1996 Baalasubramanian S, Harris CL, Donev RM et al (2004) CD59a is the primary regulator of membrane attack complex assembly in the mouse. J Immunol 173(6):3684–3692 Qin X, Dobarro M, Bedford SJ et al (2005) Further characterization of reproductive abnormalities in mCd59b knockout mice: a potential new function of mCd59 in male reproduction. J Immunol 175(10):6294–6302 Qin X, Miwa T, Aktas H et al (2001) Genomic structure, functional comparison, and tissue distribution of mouse Cd59a and Cd59b. Mamm Genome 12(8):582–589. https://doi.org/10.1007/s00335-001-2060-8 Qin X, Ferris S, Hu W, Guo F, Ziegeler G, Halperin JA (2006) Analysis of the promoters and 5’-UTR of mouse Cd59 genes, and of their functional activity in erythrocytes. Genes Immun 7(4):287–297. https://doi.org/10.1038/sj.gene.6364296 Golec E, Ekström A, Noga M et al (2022) Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets. Proc Natl Acad Sci U S A 119(24):E2120083119. https://doi.org/10.1073/pnas.2120083119 Fonseca MI, Chu SH, Hernandez MX et al (2017) Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflamm 14(1):48. https://doi.org/10.1186/s12974-017-0814-9 Shi L, Takahashi K, Dundee J et al (2004) Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus. J Exp Med 199(10):1379–1390. https://doi.org/10.1084/jem.20032207 Matsumoto M, Fukuda W, Circolo A et al (1997) Abrogation of the alternative complement pathway by targeted deletion of murine factor B. Proc Natl Acad Sci U S A 94(16):8720–8725. https://doi.org/10.1073/pnas.94.16.8720 Xu Y, Ma M, Ippolito GC, Schroeder HW Jr, Carroll MC, Volanakis JE (2001) Complement activation in factor D-deficient mice. Proc Natl Acad Sci U S A 98(25):14577–14582. https://doi.org/10.1073/pnas.261428398 Wessels MR, Butko P, Ma M, Warren HB, Lage AL, Carroll MC (1995) Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity. Proc Natl Acad Sci U S A 92(25):11490–11494. https://doi.org/10.1073/pnas.92.25.11490 Wheat WH, Wetsel R, Falus A, Tack BF, Strunk RC (1987) The fifth component of complement (C5) in the mouse. Analysis of the molecular basis for deficiency. J Exp Med 165(5):1442–1447. https://doi.org/10.1084/jem.165.5.1442 Lin F, Kaminski HJ, Conti-Fine BM, Wang W, Richmonds C, Medof ME (2002) Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection. J Clin Invest 110(9):1269–1274. https://doi.org/10.1172/jci16086 Humbles AA, Lu B, Nilsson CA et al (2000) A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406(6799):998–1001. https://doi.org/10.1038/35023175 Höpken UE, Lu B, Gerard NP, Gerard C (1996) The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 383(6595):86–89. https://doi.org/10.1038/383086a0 Gerard NP, Lu B, Liu P et al (2005) An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J Biol Chem 280(48):39677–39680. https://doi.org/10.1074/jbc.C500287200 Fu X, Ju J, Lin Z et al (2016) Target deletion of complement component 9 attenuates antibody-mediated hemolysis and lipopolysaccharide (LPS)-induced acute shock in mice. Sci Rep 6:30239. https://doi.org/10.1038/srep30239 Qin X, Hu W, Song W et al (2009) Generation and phenotyping of mCd59a and mCd59b double-knockout mice. Am J Hematol 84(2):65–70. https://doi.org/10.1002/ajh.21319 Welsh KJ, Lewis CT, Boyd S, Braun MC, Actor JK (2012) Complement factor C7 contributes to lung immunopathology caused by Mycobacterium tuberculosis. Clin Dev Immunol 2012:429675. https://doi.org/10.1155/2012/429675 Qin X, Hu W, Song W et al (2009) Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice. Am J Hematol 84(4):221–227. https://doi.org/10.1002/ajh.21363 Holt DS, Botto M, Bygrave AE, Hanna SM, Walport MJ (2001) Morgan BP (2001) Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria. Blood 98(2):442–449. https://doi.org/10.1182/blood.V98.2.442 Triantafilou K, Hughes TR, Triantafilou M, Morgan BP (2013) The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci 126(Pt 13):2903–2913. https://doi.org/10.1242/jcs.124388 Kolev M, West EE, Kunz N et al (2020) Diapedesis-induced integrin signaling via LFA-1 facilitates tissue immunity by inducing intrinsic complement C3 expression in immune cells. Immunity 52(3):513–5278. https://doi.org/10.1016/j.immuni.2020.02.006 Polack FP, Teng MN, Collins PL et al (2002) A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 196(6):859–865. https://doi.org/10.1084/jem.20020781 Bukreyev A, Yang L, Collins PL (2012) The secreted G protein of human respiratory syncytial virus antagonizes antibody-mediated restriction of replication involving macrophages and complement. J Virol 86(19):10880–10884. https://doi.org/10.1128/jvi.01162-12 Kuppan JP, Mitrovich MD, Vahey MD (2021) A morphological transformation in respiratory syncytial virus leads to enhanced complement deposition. Elife 10:e70575. https://doi.org/10.7554/eLife.70575 Song N, Li P, Jiang Y et al (2018) C5a receptor1 inhibition alleviates influenza virus-induced acute lung injury. Int Immunopharmacol 59:12–20. https://doi.org/10.1016/j.intimp.2018.03.029 Sun S, Zhao G, Liu C et al (2013) Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir Cell Mol Biol 49(2):221–230. https://doi.org/10.1165/rcmb.2012-0428OC O’Brien KB, Morrison TE, Dundore DY, Heise MT, Schultz-Cherry S (2011) A protective role for complement C3 protein during pandemic 2009 H1N1 and H5N1 influenza A virus infection. PLoS ONE 6(3):17377. https://doi.org/10.1371/journal.pone.0017377 Longhi MP, Williams A, Wise M, Morgan BP, Gallimore A (2007) CD59a deficiency exacerbates influenza-induced lung inflammation through complement-dependent and -independent mechanisms. Eur J Immunol 37(5):1266–1274. https://doi.org/10.1002/eji.200636755 Tam JCH, Bidgood SR, McEwan WA, James LC (2014) Intracellular sensing of complement C3 activates cell autonomous immunity. Science 345(6201):1256070 Mellors J, Tipton T, Longet S, Carroll M (2020) Viral evasion of the complement system and its importance for vaccines and therapeutics. Front Immunol 11:1450. https://doi.org/10.3389/fimmu.2020.01450 Wang C, Khatun MS, Zhang Z et al (2023) COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes. Commun Biol 6(1):1265. https://doi.org/10.1038/s42003-023-05626-z Hu W, Ferris SP, Tweten RK et al (2008) Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin. Nat Med 14(1):98–103 Feng D, Dai S, Liu F et al (2016) Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration. J Clin Invest 126(6):2321–2333. https://doi.org/10.1172/JCI84921 Han K, Blair RV, Iwanaga N et al (2021) Lung expression of human angiotensin-converting enzyme 2 sensitizes the mouse to SARS-CoV-2 infection. Am J Respir Cell Mol Biol 64(1):79–88. https://doi.org/10.1165/rcmb.2020-0354OC