Volume 13, Issue 2 (6-2025)                   JoMMID 2025, 13(2): 118-126 | Back to browse issues page

Ethics code: IR.SBMU.NRITLD.REC.1399.087

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Mohebbi S, Arabzadeh S, Naseri Lahiji S, Fathi Z. Remdesivir Modulates CASP8 and CASP9 Expression in COVID-19 Patients: Impact on Apoptotic Pathways and Immune Response. JoMMID 2025; 13 (2) :118-126
URL: http://jommid.pasteur.ac.ir/article-1-728-en.html
Department of Biology, Faculty of Basic Science, Ale Taha Institute of Higher Education, Tehran, Iran
Abstract:   (71 Views)
Introduction: COVID-19, caused by SARS-CoV-2, is associated with alterations in apoptotic signaling pathways, which influence disease progression and immune function. CASP8 and CASP9 are key regulators of apoptosis. This study aimed to evaluate the expression levels of the CASP8 and CASP9 genes in COVID-19 patients compared to healthy controls, and to investigate the effect of Remdesivir treatment on their expression. Methods: Blood samples were collected from 30 hospitalized patients infected with the SARS-CoV-2 Omicron variant before and after Remdesivir treatment, and from 20 healthy controls. Patients received intravenous Remdesivir therapy (200 mg on day one, followed by 100 mg daily for 4 days). RNA was extracted from blood leukocytes, and real-time quantitative PCR (qPCR) was conducted to assess gene expression, normalized to GAPDH. Results: No significant difference was observed in CASP8 expression between untreated COVID-19 patients and controls. However, CASP8 expression increased 2.5-fold in Remdesivir-treated COVID-19 patients compared to untreated patients (P < 0.001). CASP9 expression was reduced to 10% of healthy control levels in COVID-19 patients (P < 0.001) but increased to 80% of control values after Remdesivir therapy (P < 0.001). A modest positive correlation was observed between CASP8 and CASP9 expression (r = 0.333; P = 0.05), and between CASP8 expression and total white blood cell (WBC) count (r = 0.356; P = 0.05). Conclusions: Remdesivir modulates apoptosis-related gene expression, upregulating CASP8 and partially restoring CASP9 expression in COVID-19 patients. These findings suggest that Remdesivir influences apoptotic pathways, which may contribute to immune regulation during SARS-CoV-2 infection and enhance therapeutic outcomes.
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Type of Study: Original article | Subject: Microbial pathogenesis
Received: 2025/04/13 | Accepted: 2025/06/11 | Published: 2025/06/11

References
1. Zhu Z, Shi J, Li L, Wang J, Zhao Y, Ma H. Therapy targets SARS-CoV-2 infection-induced cell death. Front Immunol. 2022; 13: 870216. [DOI:10.3389/fimmu.2022.870216] [PMID] [PMCID]
2. Khajenoori Y, Murali N, Ordonio K, Ghassemzadeh K, Mar M. Comprehensive review of clinical symptoms and complications in association with COVID-19. 2020. (Preprint) [DOI:10.31219/osf.io/7x39h]
3. Baj J, Karakuła-Juchnowicz H, Teresiński G, Buszewicz G, Ciesielka M, Sitarz R, et al. COVID-19: specific and non-specific clinical manifestations and symptoms: the current state of knowledge. J Clin Med. 2020; 9 (6): 1753. [DOI:10.3390/jcm9061753] [PMCID]
4. Alonge A, Ademusire B, Epum C, Adewale B, Adefarati O. Complications of COVID-19: a systematic review and meta-analysis. J Microbiol Infect Dis. 2021; 11 (2): 45-57. [DOI:10.5799/jmid.951471]
5. Tsai PH, Lai WY, Lin YY, Luo YH, Lin YT, Chen HK, et al. Clinical manifestation and disease progression in COVID-19 infection. J Chin Med Assoc. 2021; 84 (1): 3-8. [DOI:10.1097/JCMA.0000000000000463] [PMID]
6. da Silva MM, de Lucena ASL, Paiva Júnior SSL, De Carvalho VMF, de Oliveira PSS, da Rosa MM, et al. Cell death mechanisms involved in cell injury caused by SARS-CoV-2. Rev Med Virol. 2022; 32 (3): e2292. [DOI:10.1002/rmv.2292] [PMID] [PMCID]
7. Paolini A, Borella R, De Biasi S, Neroni A, Mattioli M, Lo Tartaro D, et al. Cell death in coronavirus infections: uncovering its role during COVID-19. Cells. 2021; 10 (7): 1585. [DOI:10.3390/cells10071585] [PMID] [PMCID]
8. Naderer T, Fulcher MC. Targeting apoptosis pathways in infections. J Leukoc Biol. 2018; 103 (2): 275-85. [DOI:10.1189/JLB.4MR0717-286R] [PMID]
9. Donia A, Bokhari H. Apoptosis induced by SARS-CoV-2: can we target it? Apoptosis. 2021; 26 (1-2): 7-8. [DOI:10.1007/s10495-021-01656-2] [PMID] [PMCID]
10. André S, Picard M, Cezar R, Roux-Dalvai F, Alleaume-Butaux A, Soundaramourty C, et al. T cell apoptosis characterizes severe COVID-19 disease. Cell Death Differ. 2022; 29 (8): 1486-99. [DOI:10.1038/s41418-022-00936-x] [PMID] [PMCID]
11. Six I, Guillaume N, Jacob V, Mentaverri R, Kamel S, Boullier A, et al. The endothelium and COVID-19: an increasingly clear link brief title: endotheliopathy in COVID-19. Int J Mol Sci. 2022; 23 (11): 6196. [DOI:10.3390/ijms23116196] [PMID] [PMCID]
12. Hayden MR. An immediate and long-term complication of COVID-19 may be type 2 diabetes mellitus: the central role of β-cell dysfunction, apoptosis and exploration of possible mechanisms. Cells. 2020; 9 (11): 2475. [DOI:10.3390/cells9112475] [PMCID]
13. Bitzer M, Armeanu S, Prinz F, Ungerechts G, Wybranietz W, Spiegel M, et al. Caspase-8 and Apaf-1-independent caspase-9 activation in Sendai virus-infected cells. J Biol Chem. 2002; 277 (33): 29817-24. [DOI:10.1074/jbc.M111898200] [PMID]
14. Chen H, Ning X, Jiang Z. Caspases control antiviral innate immunity. Cell Mol Immunol. 2017; 14 (9): 736-47. [DOI:10.1038/cmi.2017.44] [PMID] [PMCID]
15. Avrutsky MI, Troy CM. Caspase-9: a multimodal therapeutic target with diverse cellular expression in human disease. Front Pharmacol. 2021; 12: 701301. [DOI:10.3389/fphar.2021.701301] [PMCID]
16. Moreno S, Alcázar B, Dueñas C, González Del Castillo J, Olalla J, Antela A. Use of antivirals in SARS-CoV-2 infection. Critical review of the role of remdesivir. Drug Des Devel Ther. 2022; 16: 827-41. [DOI:10.2147/DDDT.S356951] [PMID]
17. Sydorenko AH. Antiviral drugs in the treatment for COVID-19. Bull Ukr Med Stomatol Acad. 2023; 23 (2.2): 156-9. [DOI:10.31718/2077-1096.23.2.2.156]
18. Şimşek Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turk J Med Sci. 2020; 50 (SI-1): 611-9. [DOI:10.3906/sag-2004-145] [PMID] [PMCID]
19. Dhakal S, Charoen P, Pan-ngum W, Luvira V, Sivakorn C, Hanboonkunupakarn B, et al. Severity of COVID-19 in patients with diarrhoea: a systematic review and meta-analysis. Trop Med Infect Dis. 2023; 8 (2): 84. [DOI:10.3390/tropicalmed8020084] [PMID] [PMCID]
20. Teoh SL, Lim YH, Lai NM, Lee SWH. Directly acting antivirals for COVID-19: where do we stand? Front Microbiol. 2020; 11: 1857. [DOI:10.3389/fmicb.2020.01857] [PMID] [PMCID]
21. Kakavand G, Arabzadeh S, Mohebbi S, Saeedfar K, Abedini A, Mardani M. Impact of remdesivir treatment on factor VIII gene expression and hematological parameters in COVID-19 patients. Microb Pathog. 2025; 204: 107536. [DOI:10.1016/j.micpath.2025.107536] [PMID]
22. Arabzadeh S, Mohebbi S, Faal Z, Jalali N, Saeedfar K. Assessment of alterations in the expression of p53 and cyclin-D genes in COVID-19 patients before and after remdesivir treatment. J Genet Resour. 2025; 11 (1): 33-42.
23. Li X, Zhang Z, Wang Z, Gutiérrez-Castrellón P, Shi H. Cell deaths: involvement in the pathogenesis and intervention therapy of COVID-19. Signal Transduct Target Ther. 2022; 7 (1): 186. [DOI:10.1038/s41392-022-01043-6] [PMID] [PMCID]
24. Li S, Zhang Y, Guan Z, Li H, Ye M, Chen X, et al. SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation. Signal Transduct Target Ther. 2020; 5 (1): 235. [DOI:10.1038/s41392-020-00334-0] [PMID] [PMCID]
25. Amaral MP, Bortoluci KR. Caspase-8 and FADD: where cell death and inflammation collide. Immunity. 2020; 52 (6): 890-2. [DOI:10.1016/j.immuni.2020.05.008] [PMID]
26. Steiner S, Kratzel A, Barut GT, Lang RM, Aguiar Moreira E, Thomann L, et al. SARS-CoV-2 biology and host interactions. Nat Rev Microbiol. 2024; 22 (4): 206-25. [DOI:10.1038/s41579-023-01003-z] [PMID]
27. Zhou X, Jiang W, Liu Z, Liu S, Liang X. Virus infection and death receptor-mediated apoptosis. Viruses. 2017; 9 (11): 316. [DOI:10.3390/v9110316] [PMID] [PMCID]
28. Fritsch M, Günther SD, Schwarzer R, Albert M-C, Schorn F, Werthenbach JP, et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019; 575 (7784): 683-7. [DOI:10.1038/s41586-019-1770-6] [PMID]
29. Liu K, Stern S, Heil EL, Li L, Khairi R, Heyward S, et al. Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients. Hepatol Commun. 2023; 7 (3): e0034. [DOI:10.1097/HC9.0000000000000034] [PMID] [PMCID]
30. Martinez MA, Chen T-Y, Choi H, Hwang M, Navarathna D, Hao L, et al. Extended remdesivir infusion for persistent coronavirus disease 2019 infection. Open Forum Infect Dis. 2022; 9 (8): ofac382. [DOI:10.1093/ofid/ofac382] [PMID] [PMCID]
31. Liu K, Li Z, Li L, Heyward S, Wang SR, He L, et al. Mechanistic understanding of dexamethasone-mediated protection against remdesivir-induced hepatotoxicity. Mol Pharmacol. 2024; 106 (1): 71-82. [DOI:10.1124/molpharm.124.000894] [PMID] [PMCID]
32. Premeaux TA, Yeung ST, Bukhari Z, Bowler S, Alpan O, Gupta R, et al. Emerging insights on caspases in COVID-19 pathogenesis, sequelae, and directed therapies. Front Immunol. 2022; 13: 842740. [DOI:10.3389/fimmu.2022.842740] [PMID] [PMCID]
33. Yapasert R, Khaw-on P, Banjerdpongchai R. Coronavirus infection-associated cell death signaling and potential therapeutic targets. Molecules. 2021; 26 (24): 7459. [DOI:10.3390/molecules26247459] [PMID] [PMCID]
34. Acat M, Yıldız Gülhan P, Eröz R, Ertınmaz Özkan A, Koca O, Çınar C. Evaluation of both expression and serum protein levels of caspase-8 and mitogen-activated protein kinase 1 genes in patients with different severities of COVID-19 infection. Mol Biol Rep. 2023; 50 (4): 3241-8. [DOI:10.1007/s11033-023-08244-4] [PMID] [PMCID]
35. Yuan C, Ma Z, Xie J, Li W, Su L, Zhang G, et al. The role of cell death in SARS-CoV-2 infection. Signal Transduct Target Ther. 2023; 8 (1): 357. [DOI:10.1038/s41392-023-01580-8] [PMID] [PMCID]
36. Godwin PO, Polsonetti B, Caron MF, Oppelt TF. Remdesivir for the Treatment of COVID-19: A Narrative Review. Infect Dis Ther. 2024; 13 (1): 1-19. [DOI:10.1007/s40121-023-00900-3] [PMID] [PMCID]
37. Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M, Chen S. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020; 33(6): 1007-14. [DOI:10.1038/s41379-020-0536-x] [PMID]
38. Tummers B, Green DR. Caspase-8: regulating life and death. Immunol Rev. 2017; 277 (1): 76-89. [DOI:10.1111/imr.12541] [PMID] [PMCID]
39. Uzunova K, Filipova E, Pavlova V, Vekov T. Insights into antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine affecting the new SARS-CoV-2. Biomed Pharmacother. 2020; 131: 110668. [DOI:10.1016/j.biopha.2020.110668] [PMCID]
40. Malin JJ, Suárez I, Priesner V, Fätkenheuer G, Rybniker J. Remdesivir against COVID-19 and other viral diseases. Clin Microbiol Rev. 2020; 34 (1): e00162-20. [DOI:10.1128/CMR.00162-20] [PMID] [PMCID]
41. Bhowal C, Ghosh S, Ghatak D, De R. Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight. Mol Cell Biochem. 2023; 478 (6): 1325-43. [DOI:10.1007/s11010-022-04593-z] [PMID] [PMCID]
42. Gustine JN, Jones D. Immunopathology of hyperinflammation in COVID-19. Am J Pathol. 2021; 191 (1): 4-17. [DOI:10.1016/j.ajpath.2020.08.009] [PMID] [PMCID]
43. Green DR. Caspase activation and inhibition. cold spring harb perspect Biol. 2022; 14 (8): a041020. [DOI:10.1101/cshperspect.a041020] [PMID] [PMCID]
44. Ning X, Wang Y, Jing M, Sha M, Lv M, Gao P, et al. Apoptotic caspases suppress type I interferon production via the cleavage of cGAS, MAVS, and IRF3. Mol Cell. 2019; 74 (1): 19-31. [DOI:10.1016/j.molcel.2019.02.013]
45. Jana S, Halder S, Bhattacharya A, Bhattacharya MK, Jana K. Role of apoptosis in viral infections with special reference to COVID-19: therapeutic targets and strategies. In: Jana K, editor. Apoptosis and Human Health: Understanding Mechanistic and Therapeutic Potential. Singapore: Springer Nature Singapore; 2024. p.325-39. [DOI:10.1007/978-981-97-7905-5_15]
46. Chu H, Shuai H, Hou Y, Zhang X, Wen L, Huang X, et al. Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity. Sci Adv. 2021; 7 (25): eabf8577. [DOI:10.1126/sciadv.abf8577] [PMID]
47. Abiri E, Mirzaii M, Moghbeli M, Atashi A, Harati AA. Investigating the relationship between lymphocyte cells apoptosis and DNA damage and oxidative stress and therapeutic and clinical outcomes of COVID-19 elderly patients. BMC Infect Dis. 2024; 24 (1): 940. [DOI:10.1186/s12879-024-09734-x] [PMID] [PMCID]
48. Zhang W, Zhu C, Liao Y, Zhou M, Xu W, Zou Z. Caspase-8 in inflammatory diseases: a potential therapeutic target. Cell Mol Biol Lett. 2024; 29 (1): 130. [DOI:10.1186/s11658-024-00646-x] [PMID] [PMCID]
49. Mustafa M, Ahmad R, Tantry IQ, Ahmad W, Siddiqui S, Alam M, et al. Apoptosis: a comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells. 2024; 13 (22): 1838. [DOI:10.3390/cells13221838] [PMID] [PMCID]
50. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol. 2020; 11: 1708. [DOI:10.3389/fimmu.2020.01708]
51. Aziz M, Jacob A, Wang P. Revisiting caspases in sepsis. Cell Death Dis. 2014; 5 (11): e1526. [DOI:10.1038/cddis.2014.488] [PMID] [PMCID]
52. Qiu Y, Li Z, Lin F, Yang Y, Yang L, Li T. Comparison of the disease severity with infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants: A meta-analysis. MedComm Future Med. 2023; 2 (1): e39. [DOI:10.1002/mef2.39]
53. SeyedAlinaghi S, Afsahi AM, Mirzapour P, Afzalian A, Shahidi R, Dashti M, et al. Comparison of Omicron and Delta variants of SARS-CoV-2: a systematic review of current evidence. Infect Disord Drug Targets. 2024; 24 (7): e050324227686. [DOI:10.2174/0118715265279242240216114548] [PMID]

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Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.