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COVID-19 Mortality and the Cytokine Storm: An Added Value for APOE Genotyping

Author(s): Luis Diambra* and Reza Rastmanesh*

Volume 3, Issue 6, 2022

Published on: 19 December, 2022

Article ID: e051222211598 Pages: 6

DOI: 10.2174/2666796704666221205152504

Abstract

The new COVID-19 presents some comorbidities, such as obesity, Alzheimer’s, and coronary risk, among others. We argue that the current understanding of some of these clinical conditions may illuminate the design of future COVID-19 studies to account for a bias that may be the cause of the paradoxical associations between COVID-19 mortality and cytokine storm. Given that we know some of the genetic mechanisms behind these diseases, it is possible to circumscribe these studies to some key genes that help us understand why some patients experience a cytokine storm and what the treatment strategies might be. In this paper, we discuss the role of A2M and APOE genes. A2M encodes a multifaceted protein which is highly expressed in the liver and released to the bloodstream associated with the apolipoprotein E. This association depends on the APOE genotype. A2M has protease-clearing activity binding of a broad range of proteases, such as thrombin and Factor Xa. It also presents the ability to bind to proinflammatory ligands, like cytokines. Further, A2M acts as chaperone of misfolded substrates, like betaamyloid peptide. The last two molecular functions grant it a key role in regulating both inflammatory processes, as well as extracellular protein homeostasis. For these reasons, we conclude that A2M-APOE association will have prophylactic, therapeutic, and prognostic implications; and the proper understanding of the physiological role of APOE and A2M in controlling inflammatory processes can shed further light on the putative treatment of COVID-19-derived cytokine storm.

Keywords: APOE, A2M, SARS-CoV-2, cytokine storm, COVID-19, comorbidities, Alzheimer, coagulopathies.

Graphical Abstract

[1]
World Health Organization. COVID-19 weekly epidemiological update 86 2022.
[2]
Guan W, Liang W, Zhao Y, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: A nationwide analysis. Eur Respir J 2020; 55(5): 2000547.
[http://dx.doi.org/10.1183/13993003.00547-2020] [PMID: 32217650]
[3]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[4]
Wang Q, Hu Z. Successful recovery of severe COVID-19 with cytokine storm treating with extracorporeal blood purification. Int J Infect Dis 2020; 96: 618-20.
[http://dx.doi.org/10.1016/j.ijid.2020.05.065] [PMID: 32470601]
[5]
Kuo C-L, Pilling LC, Atkins JL, et al. APOE e4e4 genotype and mortality with COVID-19 in UK biobank. J Gerontol A Biol Sci Med Sci 2020; 75(9): 1801-3.
[6]
Kurki SN, Kantonen J, Kaivola K, et al. APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: A Finnish biobank, autopsy and clinical study. Acta Neuropathol Commun 2021; 9(1): 199.
[http://dx.doi.org/10.1186/s40478-021-01302-7] [PMID: 34949230]
[7]
Hubacek JA, Dlouha L, Dusek L, Majek O, Adamkova V. Apolipoprotein e4 allele in subjects with COVID-19. Gerontology 2021; 67(3): 320-2.
[http://dx.doi.org/10.1159/000516200] [PMID: 33965962]
[8]
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18(4): 844-7.
[http://dx.doi.org/10.1111/jth.14768] [PMID: 32073213]
[9]
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18(5): 1094-9.
[http://dx.doi.org/10.1111/jth.14817] [PMID: 32220112]
[10]
Nuñez MJ, Villalba JC, Cebrián E, et al. Venous thromboembolism in immobilized patients with dementia. Findings from the RIETE registry. Thromb Res 2012; 130(2): 173-7.
[http://dx.doi.org/10.1016/j.thromres.2012.02.006] [PMID: 22374336]
[11]
Albayati M, Grover S, Saha P, Lwaleed B, Modarai B, Smith A. Postsurgical inflammation as a causative mechanism of venous thromboembolism. Semin Thromb Hemost 2015; 41(6): 615-20.
[http://dx.doi.org/10.1055/s-0035-1556726] [PMID: 26276933]
[12]
De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000; 26(03): 305-12.
[http://dx.doi.org/10.1055/s-2000-8473] [PMID: 11011848]
[13]
Chen YL, Shou LH, Zhang ZX. Association of interleukin-18 gene polymorphism and its protein expression with the lower extremity deep venous thrombosis in the chinese han population: A case-control study. J Clin Lab Anal 2018; 32(4): e22345.
[http://dx.doi.org/10.1002/jcla.22345] [PMID: 29105174]
[14]
Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population. Atherosclerosis 2016; 246: 63-70.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.12.038] [PMID: 26761769]
[15]
Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals. Alzheimers Dement 2018; 14(1): 71-80.
[http://dx.doi.org/10.1016/j.jalz.2017.05.006] [PMID: 28774656]
[16]
Bennet AM, Di Angelantonio E, Ye Z, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298(11): 1300-11.
[http://dx.doi.org/10.1001/jama.298.11.1300] [PMID: 17878422]
[17]
Frikke-Schmidt R, Tybjærg-Hansen A, Steffensen R, Jensen G, Nordestgaard BG. Apolipoprotein E genotype: Epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease. J Am Coll Cardiol 2000; 35(5): 1192-9.
[http://dx.doi.org/10.1016/S0735-1097(00)00520-9] [PMID: 10758960]
[18]
Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105949 individuals from a white general population cohort. Eur Heart J 2019; 40(33): 2813-24.
[http://dx.doi.org/10.1093/eurheartj/ehz402] [PMID: 31236578]
[19]
Sebastiani P, Solovieff N, DeWan AT, et al. Genetic signatures of exceptional longevity in humans. PLoS One 2012; 7(1): e29848.
[http://dx.doi.org/10.1371/journal.pone.0029848] [PMID: 22279548]
[20]
Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet 2013; 132(12): 1323-38.
[http://dx.doi.org/10.1007/s00439-013-1342-z] [PMID: 23925498]
[21]
Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: New insights from epidemiology, genetics, and biology. Circ Res 2016; 118(4): 547-63.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306249] [PMID: 26892957]
[22]
Zhu S, Wang Z, Wu X, Shu Y, Lu D. Apolipoprotein E polymorphism is associated with lower extremity deep venous thrombosis: Color-flow Doppler ultrasound evaluation. Lipids Health Dis 2014; 13(1): 21.
[http://dx.doi.org/10.1186/1476-511X-13-21] [PMID: 24456740]
[23]
Ren B, Yan F, Deng Z, et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe COVID-19 in Wuhan. Circulation 2020; 142(2): 181-3.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047407] [PMID: 32412320]
[24]
Corbo RM, Scacchi R, Apolipoprotein E. APOE) allele distribution in the world. Is APOE * 4 a ‘thrifty’ allele? Ann Hum Genet 1999; 63(4): 301-10.
[http://dx.doi.org/10.1046/j.1469-1809.1999.6340301.x] [PMID: 10738542]
[25]
Bhala N, Curry G, Martineau AR, Agyemang C, Bhopal R. Sharpening the global focus on ethnicity and race in the time of COVID-19. Lancet 2020; 395(10238): 1673-6.
[http://dx.doi.org/10.1016/S0140-6736(20)31102-8] [PMID: 32401716]
[26]
Centers for Disease Control and Prevention. Provisional death counts for coronavirus disease (COVID-19) In: 2020.
[27]
1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 2015; 526: 68-74.
[28]
Gale SC, Gao L, Mikacenic C, et al. APOε4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol 2014; 134(1): 127-134.e9.
[http://dx.doi.org/10.1016/j.jaci.2014.01.032] [PMID: 24655576]
[29]
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020; 109: 102433.
[http://dx.doi.org/10.1016/j.jaut.2020.102433] [PMID: 32113704]
[30]
Krimbou L, Tremblay M, Davignon J, Cohn JS. Association of apolipoprotein E with α2-macroglobulin in human plasma. J Lipid Res 1998; 39(12): 2373-86.
[http://dx.doi.org/10.1016/S0022-2275(20)33316-2] [PMID: 9831625]
[31]
Soler-López M, Zanzoni A, Lluís R, Stelzl U, Aloy P. Interactome mapping suggests new mechanistic details underlying Alzheimer’s disease. Genome Res 2011; 21(3): 364-76.
[http://dx.doi.org/10.1101/gr.114280.110] [PMID: 21163940]
[32]
Chu CT, Howard GC, Misra UK, Pizzo S. α 2-macroglobulin: A sensor for proteolysis. Ann N Y Acad Sci 1994; 737(1 Biology of 2-): 291-307.
[http://dx.doi.org/10.1111/j.1749-6632.1994.tb44319.x] [PMID: 7524403]
[33]
French K, Yerbury JJ, Wilson MR. Protease activation of α2-macroglobulin modulates a chaperone-like action with broad specificity. Biochemistry 2008; 47(4): 1176-85.
[http://dx.doi.org/10.1021/bi701976f] [PMID: 18171086]
[34]
Borth W, Urbanski A, Prohaska R, Susanj M, Luger TA. Binding of recombinant interleukin-1 beta to the third complement component and alpha 2-macroglobulin after activation of serum by immune complexes. Blood 1990; 75(12): 2388-95.
[http://dx.doi.org/10.1182/blood.V75.12.2388.2388] [PMID: 1693530]
[35]
Matsuda T, Hirano T, Nagasawa S, Kishimoto T. Identification of alpha 2-macroglobulin as a carrier protein for IL-6. J Immunol 1989; 142(1): 148-52.
[PMID: 2462586]
[36]
Wollenberg GK, LaMarre J, Rosendal S, Gonias SL, Hayes MA. Binding of tumor necrosis factor alpha to activated forms of human plasma alpha 2 macroglobulin. Am J Pathol 1991; 138(2): 265-72.
[PMID: 1704186]
[37]
Wu SM, Patel DD, Pizzo SV. Oxidized α2-macroglobulin (α2M) differentially regulates receptor binding by cytokines/growth factors: Implications for tissue injury and repair mechanisms in inflammation. J Immunol 1998; 161(8): 4356-65.
[PMID: 9780213]
[38]
Feige JJ, Negoescu A, Keramidas M, Souchelnitskiy S, Chambaz EM. α 2-macroglobulin: A binding protein for transforming growth factor-β and various cytokines. Horm Res 1996; 45(3-5): 227-32.
[http://dx.doi.org/10.1159/000184793] [PMID: 8964589]
[39]
Ashcom JD, Tiller SE, Dickerson K, Cravens JL, Argraves WS, Strickland DK. The human alpha 2-macroglobulin receptor: Identification of a 420-kD cell surface glycoprotein specific for the activated conformation of alpha 2-macroglobulin. J Cell Biol 1990; 110(4): 1041-8.
[http://dx.doi.org/10.1083/jcb.110.4.1041] [PMID: 1691187]
[40]
Crookston KP, Webb DJ, Wolf BB, Gonias SL. Classification of alpha 2-macroglobulin-cytokine interactions based on affinity of noncovalent association in solution under apparent equilibrium conditions. J Biol Chem 1994; 269(2): 1533-40.
[http://dx.doi.org/10.1016/S0021-9258(17)42289-7] [PMID: 7507109]
[41]
Wu SM, Boyer CM, Pizzo SV. The binding of receptor-recognized α2-macroglobulin to the low density lipoprotein receptor-related protein and the α2M signaling receptor is decoupled by oxidation. J Biol Chem 1997; 272(33): 20627-35.
[http://dx.doi.org/10.1074/jbc.272.33.20627] [PMID: 9252378]
[42]
Narita M, Holtzman DM, Schwartz AL, Bu G. α2-macroglobulin complexes with and mediates the endocytosis of β-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J Neurochem 1997; 69(5): 1904-11.
[http://dx.doi.org/10.1046/j.1471-4159.1997.69051904.x] [PMID: 9349534]
[43]
Wyatt AR, Constantinescu P, Ecroyd H, et al. Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms. FEBS Lett 2013; 587(5): 398-403.
[http://dx.doi.org/10.1016/j.febslet.2013.01.020] [PMID: 23353684]
[44]
Coon KD, Myers AJ, Craig DW, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry 2007; 68(4): 613-8.
[http://dx.doi.org/10.4088/JCP.v68n0419] [PMID: 17474819]
[45]
Bojkova D, Klann K, Koch B, et al. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 2020; 583(7816): 469-72.
[http://dx.doi.org/10.1038/s41586-020-2332-7] [PMID: 32408336]
[46]
Alonso AM, Diambra L. SARS-CoV-2 codon usage bias downregulates host expressed genes with similar codon usage. Front Cell Dev Biol 2020; 8: 831.
[http://dx.doi.org/10.3389/fcell.2020.00831] [PMID: 32974353]
[47]
LaMarre J, Wolf BB, Kittler EL, Quesenberry PJ, Gonias SL. Regulation of macrophage alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma. J Clin Invest 1993; 91(3): 1219-24.
[http://dx.doi.org/10.1172/JCI116283] [PMID: 7680664]
[48]
Shen B, Yi X, Sun Y, et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell 2020; 182(1): 59-72.e15.
[http://dx.doi.org/10.1016/j.cell.2020.05.032] [PMID: 32492406]
[49]
Wu SM, Pizzo SV. Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by α 2-macroglobulin. Biochemistry 1999; 38(42): 13983-90.
[http://dx.doi.org/10.1021/bi991438i] [PMID: 10529245]
[50]
Suba Z. Prevention and therapy of COVID-19 via exogenous estrogen treatment for both male and female patients. J Pharm Pharm Sci 2020; 23(1): 75-85.
[http://dx.doi.org/10.18433/jpps31069] [PMID: 32324533]
[51]
Chen R, Tang X, Tan S, et al. Treatment of severe acute respiratory syndrome with glucosteroids: The Guangzhou experience. Chest 2006; 129(6): 1441-52.
[http://dx.doi.org/10.1378/chest.129.6.1441] [PMID: 16778260]
[52]
Tang BMP, Craig JC, Eslick GD, Seppelt I, McLean AS. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis. Crit Care Med 2009; 37(5): 1594-603.
[http://dx.doi.org/10.1097/CCM.0b013e31819fb507] [PMID: 19325471]
[53]
Khan MM, Shibuya Y, Kambara T, Yamamoto T. Role of alpha-2-macroglobulin and bacterial elastase in guinea-pig pseudomonal septic shock. Int J Exp Pathol 1995; 76(1): 21-8.
[PMID: 7537522]
[54]
Zhang Y, Wei X, Browning S, Scuderi G, Hanna LS, Wei L. Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection. Arthritis Res Ther 2017; 19(1): 175.
[http://dx.doi.org/10.1186/s13075-017-1363-4] [PMID: 28743292]

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