Papel do imunometabolismo, receptores Toll-Like e ECA 2 na COVID-19
Role of immunometabolism, Toll-Like receptors, and ACE-2 in COVID-19
Simone Cristina Soares Brandão; Emmanuelle Tenório Albuquerque Madruga Godoi; Lúcia Helena de Oliveira Cordeiro; Débora Nóbrega de Lima; Camila de Holanda Medeiros; João Paulo Vieira e Silva de Albuquerque; Maria Eduarda Lins Arraes Ramos; Romero Carvalho Coimbra Albêlo; Maria Fernanda Peixoto Matos; Emanuel Sávio Cavalcanti Sarinho
Resumo
No combate à infecção pelo coronavírus 2 da síndrome respiratória aguda grave (SARS-CoV-2), o organismo se utiliza de mecanismos da imunidade inata, dentre eles os receptores TollLike (TLR), responsáveis pela sinalização da inflamação através da liberação de mediadores químicos e recrutamento de células imunitárias. Na patologia causada pela doença do SARS-CoV-2 2019 (COVID-19), ganha especial importância o TLR-4, visto que a sua estimulação exacerbada vem sendo relacionada ao estado hiperinflamatório em fases avançadas da COVID-19. Outro receptor que desempenha um papel primordial na infecção pelo SARS-CoV-2, servindo como porta de entrada para o vírus e progressão da doença, é a enzima conversora de angiotensina 2 (ECA 2), cuja ligação com a proteína S viral causa desregulação de vários sistemas fundamentais para a homeostase, como o sistema renina-angiotensina-aldosterona. Pacientes com doenças cardiometabólicas como obesidade, diabetes, aterosclerose e hipertensão vêm sendo classificados como alto risco para desenvolver as formas graves da COVID-19, visto que o estado inflamatório, já existente nessas doenças, pode ser agravado pelo desequilíbrio metabólico causado pelo SARS-CoV-2. A elucidação desses e de outros mecanismos relacionados à fisiopatologia da COVID-19 é imprescindível para uma melhora na estratificação de risco, nas escolhas terapêuticas e no prognóstico desses pacientes. Desta forma, nesta revisão objetivamos discutir as relações entre TLR-4, ECA 2, doenças cardiometabólicas, infecção pelo SARS-CoV-2 e gravidade da COVID-19.
Palavras-chave
Abstract
In the fight against the infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the body uses mechanisms from the innate immune system, such as Toll-Like receptors (TLR), responsible for inflammation signaling through release of chemical mediators and recruitment of immune cells. In the disease caused by SARS-CoV-2 (COVID-19), TLR-4 assumes special importance because its exacerbated stimulation has been related to a hyperinflammatory state in advanced stages of COVID-19. Another receptor that plays a major role in SARS-CoV-2 infection, serving as a gateway to the virus and impacting disease progression, is angiotensin-converting enzyme 2 (ACE-2), whose binding to the viral S protein causes dysregulation of several key systems for homeostasis, such as the renin-angiotensin-aldosterone system. The elucidation of these and other mechanisms related to the pathophysiology of COVID-19 is essential for an improvement in risk stratification, therapeutic choices, and prognosis for these patients. Thus, we aimed to discuss in this review the relationships between TLR-4, ACE-2, cardiometabolic diseases, SARS-CoV-2 infection, and severity of COVID-19.
Keywords
Referências
1. Seyed Hosseini E, Riahi Kashani N, Nikzad H, Azadbakht J, Hassani Bafrani H, Haddad Kashani H. The novel coronavirus Disease-2019 (COVID-19): Mechanism of action, detection and recent therapeutic strategies. Virology. 2020;551:1-9.
2. Aboudounya MM, Heads RJ. COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation. Mediators Inflamm. 2021;2021.
3. Brandão SCS, Silva EAGBB, Ramos JOX, Melo LMMP, Sarinho ESC. COVID-19, imunidade, endotélio e coagulação: compreenda a interação. Recife; 2020. p. 70.
4. SARS-CoV-2 Variants Classifications and Definitions. Centers for Disease Control and Prevention, 2021 [Internet]. Disponível em:
5. Cruvinel WM, Júnior DM, Araújo JAP, Catelan TTT, Souza AWS, Silva NP, et al. Sistema Imunitário – Parte I. Fundamentos da imunidade inata com ênfase nos mecanismos moleculares e celulares da resposta inflamatória. Rev Bras Reumatol. 2010;50(4):434-61.
6. Ferraz EG, Silveira BBB, Sarmento VA, Santos JN. Receptores Toll-Like: ativação e regulação da resposta imune. RGO - Revista Gaúcha Odontol. 2011;59(3):483-90.
7. Bártholo RM, Bártholo TP. Imunidade inata e a importância dos receptores Toll-similar. Pulmão RJ [Internet]. 2009;Supl 2:S2-S8. Disponível em: http://www.sopterj.com.br/wp-content/themes/_sopterj_redesign_2017/_revista/2009/suplemento-pneumonia/ imunidade-inata-e-a-importancia-dos-receptores-toll-similar.pdf
8. Brandão SCS, Ramos JOX, Dompieri LT, Godoi ETAM, Figueiredo JL, Sarinho ESC, et al. Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities? Cytokine Growth Factor Rev. 2021 Apr;58:102-10. doi: 10.1016/j.cytogfr.2020.09.002.
9. Francischetti EA, Francischetti A, Abreu VG. A emergência de um novo modulador cardiovascular - A 2a enzima de conversão da Angiotensina 2 (ECA2). Rev SOCERJ. 2005;18(1):36-40.
10. Brandão S, Godoi E, Cordeiro L, Bezerra C, Ramos J, Arruda G, et al. Obesidade e Risco de COVID-19 Grave [Internet]. Repositório Digital da UFPE. 2020. 112 p. Disponível em: https://repositorio.ufpe.br/handle/123456789/37572.
11. Silva TF, Vaz TM, Souza MS, Ferreira, LP, Limborço Filho M, Fontes MAP, et al. O envolvimento do sistema Renina-Angiotensina nas disfunções cardiovasculares e seus recursos farmacológicos. Rev Cient Multidisciplinar Núcleo do Conhecimento. 2019;2(11):181‑96. doi 10.32749/nucleodoconhecimento.com.br/saude/reninaangiotensina.
12. Cunha RS, Ferreira AVL. Sistema renina-angiotensinaaldosterona e lesão vascular hipertensiva. Rev Bras Hipertens. 2000;3(3):282‑92.
13. Gonsalez SR, Ferrão FM, Souza AM, Lowe J, Morcillo LSL. Inappropriate activity of local renin-angiotensin-aldosterone system during high salt intake: impact on the cardio-renal axis. J Bras Nefrol. 2018;40(2):170-8. Referências
14. Naves LA, Vilar L, Costa ACF, Domingues L, Casulari LA. Distúrbios na secreção e ação do hormônio antidiurético. Arq Bras Endocrinol Metabol. 2003;47(4):467-81.
15. Scholz JR, Lopes MACQ, Saraiva JFK, Colombo FC. COVID19, renin-angiotensin system, angiotensin-converting enzyme 2, and nicotine: What is the interrelation? Arq Bras Cardiol. 2020;115(4):708-11.
16. Mehrabadi ME, Hemmati R, Tashakor A, Homaei A, Yousefzadeh M, Hemati K, et al. Induced dysregulation of ACE2 by SARS-CoV-2 plays a key role in COVID-19 severity. Biomed Pharmacother. 2021 May;137:111363. doi: 10.1016/j.biopha.2021.111363.
17. Kuriakose J, Montezano AC, Touyz RM. ACE2/Ang-(1-7)/Mas1 axis and the vascular system: vasoprotection to COVID-19-associated vascular disease. Clin Sci. 2021;135(2):387‑407.
18. Lima CMAO. Information about the new coronavirus disease (COVID-19). Radiol Bras. 2020;53(2):v–vi. doi: 10.1590/0100-3984.2020.53.2e1.
19. Uzunian A. Coronavirus SARS-CoV-2 and Covid-19. J Bras Patol e Med Lab. 2020;56:1-4.
20. Pinheiro ARDO, De Freitas SFT, Corso ACT. Uma abordagem epidemiológica da obesidade. Rev Nutr. 2004;17(4):523-33.
21. Sippel C, Bastian RMA, Giovanella J, Faccin C, Contini V, Dal Bosco SM. Processos inflamatórios da obesidade. Rev Atenção à Saúde. 2014;12(42):48-56.
22. Jensen MD. Visceral fat: culprit or canary? Endocrinol Metab Clin North Am. 2020;49(2):229-37.
23. Prado WL, Lofrano MC, Oyama LM, Dâmaso AR. Obesidade e adipocinas inflamatórias: implicações práticas para a prescrição de exercício. Rev Bras Med Esporte. 2009;15(5). doi: 10.1590/ S1517-86922009000600012.
24. Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA, et al. Obesity, fat mass and immune system: Role for leptin. Front Physiol. 2018;9:640. doi: 10.3389/ fphys.2018.00640.
25. Michalakis K, Ilias I. SARS-CoV-2 infection and obesity: Common inflammatory and metabolic aspects. Diabetes Metab Syndr Clin Res Rev [Internet]. 2020;14(4):469-71. Disponível em: https://doi.org/10.1016/j.dsx.2020.04.033
26. Petrakis D, Margin D, Tsarouhas K, Tekos F, Stan M, Nikitovic D, et al. Obesity ‑ a risk factor for increased COVID‑19 prevalence, severity and lethality (Review). Mol Med Rep. 2020;22(1):9-19.
27. Costa TRM, Correia RS, Silva PHS, Lópes Barbosa GS, Oliveira LM, Cruz VT, et al. A obesidade como coeficiente no agravamento de pacientes acometidos por COVID-19. Res Soc Dev. 2020;9(9):e395997304.
28. Palaiodimos L, Kokkinidis DG, Li W, Karamanis D, Ognibene J, Arora S, et al. Severe obesity is associated with higher in-hospital mortality in a cohort of patients with COVID-19 in the Bronx, New York. Metabolism [Internet]. 2020;108:154262. Disponível em: https://doi.org/10.1016/j.metabol.2020.154262
29. Apovian CM. Obesity: definition, comorbidities, causes, and burden. Am J Manag Care. 2016;22(7):s176-85.
30. States U, December M, Kompaniyets L, Goodman AB, Belay B, Freedman DS, et al. Body Mass Index and Risk for COVID-19 – Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death – United States, March – December 2020. MMWR Morb Mortal Wkly Rep. 2021;70:355-61. doi: 10.15585/mmwr.mm7010e4external icon.
31. Codo AC, Davanzo GG, Monteiro LB, de Souza GF, Muraro SP, Virgilio-da-Silva JV, et al. Elevated Glucose Levels Favor SARSCoV-2 Infection and Monocyte Response through a HIF-1α/ Glycolysis-Dependent Axis. Cell Metab. 2020;32(3):437-446.e5.
32. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020;1456-74.
33. Mori J, Oudit GY, Lopaschuk GD. SARS-CoV-2 perturbs the reninangiotensin system and energy metabolism. Am J Physiol Endocrinol Metab. 2020;319(1):E43-7.
34. Underwood PC, Adler GK. The renin angiotensin aldosterone system and insulin resistance in humans. Curr Hypertens Rep. 2013;15(1):59-70.
35. Aminian A, Tu C. Association of Bariatric Surgery with Clinical Outcomes of SARS-CoV-2 Infection: a Systematic Review and Meta-analysis in the Initial Phase of COVID-19 Pandemic. Obes Surg. 2021 Jan 8:1-7. doi: 10.1007/s11695-020-05213-9.
36. Brandão SCS, Godoi ETAM, Ramos JOX, Melo LMMP, Dompieri LT, Brindeiro Filho DF, et al. The Role of the Endothelium in Severe COVID-19. Arq Bras Cardiol. 2020;115(6):1184-9. doi: 10.36660/ abc.20200643.
37. Wang Y, Tikellis C, Thomas MC, Golledge J. Angiotensin converting enzyme 2 and atherosclerosis. Atherosclerosis [Internet]. 2013;226(1):3-8. doi: 10.1016/j.atherosclerosis.2012.08.018.
38. Zhang YH, Zhang YH, Dong XF, Hao QQ, Zhou XM, Yu QT, et al. ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response. Inflamm Res. 2015;64(3-4):253-60. doi: 10.1007/s00011-015-0805-1.
39. Castro-Chaves P, Cerqueira R, Pintalhao M, Leite-Moreira AF. New pathways of the renin-angiotensin system: The role of ACE2 in cardiovascular pathophysiology and therapy. Expert Opin Ther Targets. 2010;14(5):485-96.
40. Zhang C, Zhao YX, Zhang YH, Zhu L, Deng BP, Zhou ZL, et al. Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells. Proc Natl Acad Sci USA. 2010;107(36):15886-91.
41. Thatcher SE, Zhang X, Howatt DA, Lu H, Gurley SB, Daugherty A, et al. Angiotensin-converting enzyme 2 deficiency in whole body or bone marrow-derived cells increases atherosclerosis in low-density lipoprotein receptor -/- mice. Arterioscler Thromb Vasc Biol. 2011;31(4):758-65.
42. Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, et al. Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circ Res. 2010;107(7):888-97.
43. Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, et al. Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol - Hear Circ Physiol. 2008;295(4):1377-84.
44. Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol [Internet]. 2020;7(8):e575-82. doi: 10.1016/S2352-3026(20)30216-7.
45. Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science. 2020;369(6501):256-7. doi: 10.1126/science.abb0762.
46. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.
47. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9. doi: 10.1001/jama.2020.1585.
48. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID19 in Wuhan, China: a retrospective cohort study. Lancet [Internet]. 2020;395(10229):1054-62. doi: 10.1016/S0140-6736(20)30566-3.
49. COVID-19 e MICI. Igibd [site da Internet]. 2020. Disponível em: https://igibd.it/ .
50. Lippi G, Wong J, Henry BM. Hypertension in patients with coronavirus disease 2019 (COVID-19): A pooled analysis. Polish Arch Intern Med. 2020;130(4):304-9.
51. Schiffrin EL, Flack JM, Ito S, Muntner P, Webb RC. Hypertension and COVID-19. Am J Hypertens. 2020;33(5):373-4.
52. Tadic M, Cuspidi C, Mancia G, Dell’Oro R, Grassi G. COVID-19, hypertension and cardiovascular diseases: Should we change the therapy? Pharmacol Res [Internet]. 2020;158(May):104906. doi: 10.1016/j.phrs.2020.104906.
53. Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, et al. Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality among Patients with Hypertension Hospitalized with COVID-19. Circ Res. 2020;126(12):1671-81.
54. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol [Internet]. 2020;17(5):259-60. doi: 10.1038/ s41569-020-0360-5.
55. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ [Internet]. 2020;368(December 2019):1–14. doi:10.1136/bmj.m1091.
56. Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M. Hypertension and kidneys: Unraveling complex molecular mechanisms underlying hypertensive renal damage. J Hum Hypertens [Internet]. 2014;28(2):74-9. doi: 10.1038/jhh.2013.55.
57. De Batista PR, Palacios R, Martín A, Hernanz R, Médici CT, Silva MASC, et al. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production. PLoS One. 2014;9(8).
58. Lopes RD, Macedo AVS, de Barros e Silva PGM, Moll-Bernardes RJ, Feldman A, D’Andréa Saba Arruda G, et al. Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–The BRACE CORONA Trial. Am Heart J. 2020;226:49-59.
59. Lopes RD, Macedo AVS, De Barros e Silva PGM, Moll-Bernardes RJ, Dos Santos TM, Mazza L, et al. Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and out of the Hospital in Patients Admitted with COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(3):254-64. doi: 10.1001/jama.2020.25864.
60. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76(April):14-20.
61. Leung JM, Yang CX, Sin DD. COVID-19 and nicotine as a mediator of ACE-2. Eur Respir J. 2020;55(2001261).
62. Russo P, Bonassi S, Giacconi R, Malavolta M, Tomino C, Maggi F. COVID-19 and smoking: Is nicotine the hidden link? Eur Respir J. 2020;55(6):5-9.
63. Farsalinos K, Angelopoulou A, Alexandris N, Poulas K. COVID-19 and the nicotinic cholinergic system. Eur Respir J. 2020;56(1):2001589. doi: 10.1183/13993003.01589-2020.
64. Andersson J. The inflammatory reflex - Introduction. J Intern Med. 2005;257(2):122-5.
65. Kalamida D, Poulas K, Avramopoulou V, Fostieri E, Lagoumintzis G, Lazaridis K, et al. Muscle and neuronal nicotinic acetylcholine receptors: Structure, function and pathogenicity. FEBS J. 2007;274(15):3799-845.
66. Rojas M, Acosta-Ampudia Y, Monsalve DM, Ramírez-Santana C, Anaya JM. How Important Is the Assessment of Soluble ACE-2 in COVID-19? Am J Hypertens. 2021;34(3):296-297. doi: 10.1093/ajh/hpaa178.
67. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: A potential approach for coronavirus infection therapy? Clin Sci. 2020;134(5):543-5.
68. Guo J, Huang Z, Lin L, Lv J. Coronavirus Disease 2019 (COVID19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc. 2020;9(7):e016219.
Submetido em:
15/03/2021
Aceito em:
25/03/2021
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email