EXPRESSION PROFILE OF MIR-9, MIR-138, MIR-424, MIR-155 AND CTLA-4 IN THE BLOOD MONONUCLEAR CELLS OF PATIENTS WITH SARS COV-2 INFECTION

Main Article Content

Ali Abdulkadhim Jasim Al-Badri
Mohammad Khalaj-Kondori
Mohammad Ali Hosseinpour Feizi
Mehdi Haghi

Keywords

miR-9, miR-138, miR-424, miR-155, CTLA-4, SARS Cov-2, Biomarker, Gene expression

Abstract

Background: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the pathogen that causes COVID-19, a highly infectious illness. More research is being done on the potential of host biomarkers as diagnostic and prognostic tools for COVID-19. MicroRNAs have been shown to be essential for both the pathogenicity of coronavirus and the host's antiviral responses. Our aim was to assess the blood mononuclear cells expression profiles of mir-9, mir-138, mir-424, mir-155 and CTLA-4, and their association with the clinicopathological features of the patients with SARS CoV-2 infection. 


Method: This case-control study included 66 SARS-CoV-2 positive patients in the chronic and active phase of the disease and a healthy group of 41 people matched for age and sex. Blood samples were taken from the subjects and total RNA was purified from the peripheral blood mononuclear cells. The qRT-PCR was used to reveal the expression profile of miR-9, miR-138, miR-424, miR-155, and CTLA-4 genes, and compared between the patient and control groups. The diagnostic potential of CTLA-4 and miRNAs was assessed using ROC curve analysis.


Results: This investigation demonstrated a significant increase in the expression levels of miR-9, miR-138, miR-424, miR-155, and CTLA-4 (P < 0.0001) in SARS-CoV-2 patients compared to the healthy controls. We found that the expression levels of miR-9, miR-138, and miR-424 were positively correlated with CRP (p value=0.000) in the patients group. Also, a significant negative correlation was obtained between the expression of miR-9 and ESR (p-value = 0.040) in the patients group. Furthermore, the results of the ROC curve analysis indicated that the expression levels of miR-9, miR-138, miR-424, miR-155, and CTLA-4 in the blood mononuclear cells could distinguish the SARS-CoV-2 patients from healthy controls.


Conclusion: Expressions of miR-9, miR-138, miR-424, miR-155, and CTLA-4 were upregulated in COVID-19 which might be considered as potential molecular biomarkers for SARS-CoV-2 diagnosis.

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References

1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (London, England). 2020;395(10223):507-13.
2. Bradley BT, Maioli H, Johnston R, Chaudhry I, Fink SL, Xu H, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet (London, England). 2020;396(10247):320-32.
3. Chow JT, Salmena L. Prediction and Analysis of SARS-CoV-2-Targeting MicroRNA in Human Lung Epithelium. Genes. 2020;11(9).
4. Farr RJ, Rootes CL, Stenos J, Foo CH, Cowled C, Stewart CR. Detection of SARS-CoV-2 infection by microRNA profiling of the upper respiratory tract. PloS one. 2022;17(4):e0265670.
5. Guarnieri JW, Dybas JM, Fazelinia H, Kim MS, Frere J, Zhang Y, et al. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Science translational medicine. 2023;15(708):eabq1533.
6. Meydan C, Shenhar-Tsarfaty S, Soreq H. MicroRNA Regulators of Anxiety and Metabolic Disorders. Trends in molecular medicine. 2016;22(9):798-812.
7. Jia R, Yan L, Guo J. Enhancing the immunogenicity of a DNA vaccine against Streptococcus mutans by attenuating the inhibition of endogenous miR-9. Vaccine. 2020;38(6):1424-30.
8. Mirzaei R, Mahdavi F, Badrzadeh F, Hosseini-Fard SR, Heidary M, Jeda AS, et al. The emerging role of microRNAs in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. International immunopharmacology. 2021;90:107204.
9. Liu W, Zheng X, Wang J, He Q, Li J, Zhang Z, et al. MicroRNA-138 Regulates T-Cell Function by Targeting PD-1 in Patients with Hepatitis B Virus-Related Liver Diseases. Laboratory medicine. 2021;52(5):439-51.
10. Skafi N, Fayyad-Kazan M, Badran B. Immunomodulatory role for MicroRNAs: Regulation of PD-1/PD-L1 and CTLA-4 immune checkpoints expression. Gene. 2020;754:144888.
11. Li G, Ma Q, Wang R, Fan Z, Tao Z, Liu P, et al. Diagnostic and Immunosuppressive Potential of Elevated Mir-424 Levels in Circulating Immune Cells of Ischemic Stroke Patients. Aging and disease. 2018;9(2):172-81.
12. Xu J, Wang J, He Z, Chen P, Jiang X, Chen Y, et al. LncRNA CERS6-AS1 promotes proliferation and metastasis through the upregulation of YWHAG and activation of ERK signaling in pancreatic cancer. Cell death & disease. 2021;12(7):648.
13. Bautista-Becerril B, Pérez-Dimas G, Sommerhalder-Nava PC, Hanono A, Martínez-Cisneros JA, Zarate-Maldonado B, et al. miRNAs, from Evolutionary Junk to Possible Prognostic Markers and Therapeutic Targets in COVID-19. Viruses. 2021;14(1).
14. Eyileten C, Wicik Z, Simões SN, Martins-Jr DC, Klos K, Wlodarczyk W, et al. Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19. RNA biology. 2022;19(1):963-79.
15. Haroun RA, Osman WH, Amin RE, Hassan AK, Abo-Shanab WS, Eessa AM. Circulating plasma miR-155 is a potential biomarker for the detection of SARS-CoV-2 infection. Pathology. 2022;54(1):104-10.
16. Mortaz E, Jamaati H, N KD, Sheikhzade H, Hashemian SM, Roofchayee ND, et al. Changes in PD-1- and CTLA-4-bearing blood lymphocytes in ICU COVID-19 patients treated with Favipiravir/Kaletra or Dexamethasone/Remdesivir: a pilot study. Iranian journal of allergy, asthma, and immunology. 2023;22(1):99-109.
17. Lingel H, Brunner-Weinzierl MC. CTLA-4 (CD152): A versatile receptor for immune-based therapy. Seminars in immunology. 2019;42:101298.
18. Furukawa NW, Brooks JT, Sobel J. Evidence Supporting Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 While Presymptomatic or Asymptomatic. Emerging infectious diseases. 2020;26(7).
19. Jones DL, Baluja MQ, Graham DW, Corbishley A, McDonald JE, Malham SK, et al. Shedding of SARS-CoV-2 in feces and urine and its potential role in person-to-person transmission and the environment-based spread of COVID-19. The Science of the total environment. 2020;749:141364.
20. McGowan K, Simpson KJ, Petrik J. Expression Profiles of Exosomal MicroRNAs from HEV- and HCV-Infected Blood Donors and Patients: A Pilot Study. Viruses. 2020;12(8).
21. Johansson MA, Quandelacy TM, Kada S, Prasad PV, Steele M, Brooks JT, et al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA network open. 2021;4(1):e2035057.
22. Khodavirdipour A, Piri M, Jabbari S, Khalaj-Kondori M. Potential of CRISPR/Cas13 System in Treatment and Diagnosis of COVID-19. Global medical genetics. 2021;8(1):7-10.
23. Rehman A, Xing H, Adnan Khan M, Hussain M, Hussain A, Gulzar N. Emerging technologies for COVID (ET-CoV) detection and diagnosis: Recent advancements, applications, challenges, and future perspectives. Biomedical signal processing and control. 2023;83:104642.
24. Fani MA-O, Zandi M, Ebrahimi S, Soltani S, Abbasi S. (1746-0794 (Print)).
25. Arisan ED, Dart A, Grant GH, Arisan S, Cuhadaroglu S, Lange S, et al. The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities. Viruses. 2020;12(6).
26. Ghasemi T, Khalaj-Kondori M, Hosseinpour Feizi MA, Asadi P. Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG, and hypomethylation of TRPM2-AS1 promoter in colorectal cancer. Cell biology international. 2021;45(12):2464-78.
27. Ahangar NK, Hemmat N, Khalaj-Kondori M, Shadbad MA, Sabaie H, Mokhtarzadeh A, et al. The Regulatory Cross-Talk between microRNAs and Novel Members of the B7 Family in Human Diseases: A Scoping Review. Int J Mol Sci. 2021;22(5).
28. Abu-Izneid T, AlHajri N, Ibrahim AM, Javed MN, Salem KM, Pottoo FH, et al. Micro-RNAs in the regulation of immune response against SARS CoV-2 and other viral infections. Journal of advanced research. 2021;30:133-45.
29. Hu J, Stojanović J, Yasamineh S, Yasamineh P, Karuppannan SK, Hussain Dowlath MJ, et al. The potential use of microRNAs as a therapeutic strategy for SARS-CoV-2 infection. Archives of virology. 2021;166(10):2649-72.
30. Farshbaf A, Mohtasham N, Zare R, Mohajertehran F, Rezaee SA. Potential therapeutic approaches of microRNAs for COVID-19: Challenges and opportunities. Journal of oral biology and craniofacial research. 2021;11(2):132-7.
31. Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(13):5282-7.
32. Thiele S, Wittmann J, Jäck HM, Pahl A. miR-9 enhances IL-2 production in activated human CD4(+) T cells by repressing Blimp-1. European journal of immunology. 2012;42(8):2100-8.
33. Shirani F, Baghi M, Rostamian Delavar M, Shoaraye Nejati A, Eshaghiyan A, Nasr-Esfahani MH, et al. Upregulation of miR-9 and miR-193b over human Th17 cell differentiation. Molecular genetics & genomic medicine. 2020;8(12):e1538.
34. Pinto S, Cunha C, Barbosa M, Vaz AR, Brites D. Exosomes from NSC-34 Cells Transfected with hSOD1-G93A Are Enriched in miR-124 and Drive Alterations in Microglia Phenotype. Frontiers in neuroscience. 2017;11:273.
35. Liu W, Zheng X, Wang J, He Q, Li J, Zhang Z, et al. MicroRNA-138 Regulates T-Cell Function by Targeting PD-1 in Patients with Hepatitis B Virus–Related Liver Diseases. Laboratory medicine. 2021;52(5):439-51.
36. Gambardella J, Sardu C, Morelli MB, Messina V, Marfella R, Maggi P, et al. Abstract 221: Exosomal MicroRNAs Drive Tromboembolism in Covid-19. Circulation. 2020;142(Suppl_4):A221-A.
37. Kassif-Lerner R, Zloto K, Rubin N, Asraf K, Doolman R, Paret G, et al. miR-155: A Potential Biomarker for Predicting Mortality in COVID-19 Patients. Journal of personalized medicine. 2022;12(2).
38. Gaytán-Pacheco N, Ibáñez-Salazar A, Herrera-Van Oostdam AS, Oropeza-Valdez JJ, Magaña-Aquino M, Adrián López J, et al. miR-146a, miR-221, and miR-155 are Involved in Inflammatory Immune Response in Severe COVID-19 Patients. Diagnostics (Basel, Switzerland). 2022;13(1).
39. Jebbawi F, Fayyad-Kazan H, Merimi M, Lewalle P, Verougstraete JC, Leo O, et al. A microRNA profile of human CD8(+) regulatory T cells and characterization of the effects of microRNAs on Treg cell-associated genes. Journal of translational medicine. 2014;12:218.
40. Toor SM, Saleh R, Sasidharan Nair V, Taha RZ, Elkord E. T-cell responses and therapies against SARS-CoV-2 infection. Immunology. 2021;162(1):30-43.