Razvoj produženog KOVID-a kao posledice kompleksnog odnosa između Epštajn-Bar virusa i našeg imunskog sistema

  • Ana Banko Univerzitet u Beogradu, Medicinski fakultet, Institut za mikrobiologiju i imunologiju, Beograd, Srbija
Ključne reči: EBV, SARS-CoV-2, long COVID-19, koinfekcija, reaktivacija

Sažetak


Uvod: Patofiziološki osnov razvoja produženog COVID-a (engl. Long COVID, LC) još uvek je nedovoljno poznat. Međutim, sindrom zamora nakon infekcije viđen je i ranije, kod drugih patogenima uključujući Epstein-Barr virus (EBV). Uzimajući u obzir rezervoare EBV kod pacijenata sa COVID-19, ovaj pregledni rad ima za cilj opis aktuelnih saznanja u vezi sa ulogom EBV u razvoju LC i sa potencijalnom dijagnostičkom implementacijom parametara EBV infekcije.

EBV infekcija: Nakon primarne litičke infekcije epitelnih orofaringealnih i nazofaringealnih ćelija, EBV uspostavlja veoma složen mehanizam doživotnog preživljavanja u B limfocitima. Latentna infekcija sa povremenim reaktivacijama stalno stimuliše imuni odgovor domaćina. Kod osoba sa imunološkim disbalansom, uključujući COVID-19, to može izazvati dugoročne posledice.

EBV i COVID-19: Aktivna EBV infekcija najrasprostranjenija je infekcija među ostalim humanim herpesvirusima kod COVID-19 pacijenata (41%). Takođe je prijavljena korelacija između nedostatka sposobnosti za regulaciju EBV izazvane limfocitopenije, povećanja EBV viremije i komplikacija COVID-19.

EBV i Long COVID: Prisustvo EBV DNK tokom akutne infekcije SARS-CoV-2 pokazalo se kao prediktor  simptoma do 60 dana nakon COVID-19. Povezanost između EBV infekcije i simptoma kao što su “moždana magla”, umor, artralgija i osip na koži prethodno je opisana u postinfekcijskim posledicama ME/CFS. Anti-EBV EA-D IgG antitela pokazana su kod dve trećine LC ispitanika. Povećanje nivoa anti-EBNA1 IgG mesecima nakon početka COVID-19 u rekonvalescentnoj LC populaciji mogu poslužiti kao potencijalni marker reaktivacije EBV-a u vreme akutne infekcije SARS-CoV-2. Neki autori su takođe uspeli da pokažu seropozitivnost anti-EBV VCA IgM kod polovine pacijenata sa COVID-19 što ukazuje na koinfekciju ili reaktivaciju EBV.

Zaključak: LC je multisistemska bolest bez definisanog spektra dijagnostičkih i terapijskih mogućnosti. Dok reaktivacija EBV sama ili zajedno sa drugim faktorima rizika pokreće simptome LC, neophodne su dalje prospektivne studije koje uključuju različite kohorte i rezervoare tkiva u cilju razumevanja osnovnih bioloških procesa.

Reference

1. Post COVID-19 condition (Long COVID) [Internet]. [cited 2023 Nov 13]. Available from: https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
2. Astin R, Banerjee A, Baker MR, Dani M, Ford E, Hull JH, et al. Long COVID: mechanisms, risk factors and recovery. Exp Physiol. 2023;108(1):12–27.
3. Proal AD, VanElzakker MB. Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front Microbiol. 2021;12:698169.
4. Global Burden of Disease Long COVID Collaborators; Wulf Hanson S, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C, Ballouz T, Blyuss O, Bobkova P, Bonsel G, Borzakova S, Buonsenso D, Butnaru D, Carter A, Chu H, De Rose C, Diab MM, Ekbom E, El Tantawi M, Fomin VT. Estimated Global Proportions of Individuals with Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022;328(16):1604–15.
5. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid - Mechanisms, risk factors, and management. BMJ. 2021;374:n1648.
6. Proal A, Marshall T. Myalgic encephalomyelitis/chronic fatigue syndrome in the era of the human microbiome: Persistent pathogens drive chronic symptoms by interfering with host metabolism, gene expression, and immunity. Front Pediatr. 2018;6:373.
7. Poenaru S, Abdallah SJ, Corrales-Medina V, Cowan J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Ther Adv Infect Dis. 2021;8:1–16.
8. Vojdani A, Vojdani E, Saidara E, Maes M. Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID. Viruses. 2023;15(2):400.
9. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: Biology and clinical disease. Cell. 2022;185(20):3652–70.
10. Sternbæk L, Draborg AH, Østerlund MT, Iversen L V., Troelsen L, Theander E, et al. Increased antibody levels to stage-specific Epstein–Barr virus antigens in systemic autoimmune diseases reveal a common pathology. Scand J Clin Lab Invest. 2019;79(1–2):7–16.
11. Shafiee A, Aghajanian S, Athar MMT, Gargari OK. Epstein–Barr virus and COVID-19. J Med Virol. 2022;94(9):4040–2.
12. Cox BS, Alharshawi K, Mena-Palomo I, Lafuse WP, Ariza ME. EBV/HHV-6A dUTPases contribute to myalgic encephalomyelitis/chronic fatigue syndrome pathophysiology by enhancing T FH cell differentiation and extrafollicular activities. JCI Insight. 2022;7(11):e158193.
13. Smith C, Khanna R. Immune regulation of human herpesviruses and its implications for human transplantation. Am J Transplant. 2013;13(SUPPL. 3):9–23.
14. Banko A, Miljanovic D, Cirkovic A. Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field. Int J Infect Dis. 2023;130:108–25.
15. Majtanova N, Kriskova P, Keri P, Fellner Z, Majtan J, Kolar P. Herpes simplex keratitis in patients with SARS-CoV-2 infection: A series of five cases. Med. 2021;57:412.
16. Roncati L, Lusenti B, Nasillo V, Manenti A. Fatal SARS-CoV-2 coinfection in course of EBV-associated lymphoproliferative disease. Ann Hematol. 2020;99(8):1945–6.
17. Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022;185(5):881-895.e20.
18. Ruiz-Pablos M, Paiva B, Montero-Mateo R, Garcia N, Zabaleta A. Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol. 2021;12:656797.
19. Cardozo CM, Hainaut P. Viral strategies for circumventing p53: The case of severe acute respiratory syndrome coronavirus. Curr Opin Oncol. 2021;33(2):149–58.
20. Nunn AVW, Guy GW, Botchway SW, Bell JD. SARS-CoV-2 and EBV; the cost of a second mitochondrial “whammy”? Immun Ageing. 2021;18(1):40.
21. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long covid prevalence and its relationship to epstein-barr virus reactivation. Pathogens. 2021;10:763.
22. Peluso MJ, Deveau TM, Munter SE, Ryder D, Buck A, Beck-Engeser G, et al. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J Clin Invest. 2023;133(3):e163669.
23. Klutts JS, Ford BA, Perez NR, Gronowski AM. Evidence-based approach for interpretation of Epstein-Barr virus serological patterns. J Clin Microbiol. 2009 Oct;47(10):3204–10.
24. Lanz T V., Brewer RC, Ho PP, Moon JS, Jude KM, Fernandez D, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321–7.
25. Robbiani, Davide F CG, Muecksch F, Lorenzi JCC, Wang Z, Cho A, Agudelo M, et al. Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals. Nature [Internet]. 2020;584(7821):437–42. Available from: https://datadryad.org/stash/dataset/doi:10.5061/dryad.35ks2
26. Chen T, Song J, Liu H, Zheng H, Chen C. Positive Epstein–Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep. 2021;11:10902.
27. Klein J, Wood J, Jaycox J, Lu P, Dhodapkar RM, Gehlhausen JR, et al. Distinguishing features of Long COVID identified through immune profiling. medRxiv Prepr Serv Heal Sci. 2022;623(7985):139–48.
28. Rousseau BA, Bhaduri-McIntosh S. Inflammation and Epstein–Barr Virus at the Crossroads of Multiple Sclerosis and Post-Acute Sequelae of COVID-19 Infection. Viruses. 2023;15(4):949.
29. Burton EM, Goldbach-Mansky R, Bhaduri-Mcintosh S. A promiscuous inflammasome sparks replication of a common tumor virus. Proc Natl Acad Sci U S A. 2020;117(3):1722–30.
30. Hashimoto K. Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis. Mol Psychiatry. 2023;
31. Ariza ME. Myalgic encephalomyelitis/chronic fatigue syndrome: The human herpesviruses are back! Biomolecules. 2021;11(2):185.
32. Halpin P, Williams M, Klimas N, Fletcher M, Barnes Z, Ariza M. Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology. J Med Virol. 2017;89(9):1636–45.
33. Ruiz-Pablos M, Paiva B, Zabaleta A. Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID? J Transl Med. 2023;21(1):633.
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2023/12/19
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