Epigenetic Regulation of the TLR7 Gene and Its Correlation with Immune Dysregulation in Post-COVID Syndrome: TLR7 Gene and Its Correlation with Immune Dysregulation in Post-COVID Syndrome

Beenish Khalid; Saeeda Baig; Aliya Jafri; Ghazala Masood Farrukh; Sobia Khan Nabeel; Hina Faisal

doi:10.54393/pjhs.v6i9.3455

Authors

Beenish Khalid Department of Biochemistry, Hamdard College, Karachi, Pakistan
Saeeda Baig Department of Biochemistry, Ziauddin University, Karachi, Pakistan
Aliya Jafri Department of Biochemistry, Jinnah Sindh Medical University, Karachi, Pakistan
Ghazala Masood Farrukh Department of Physiology, Dow University of Health Sciences, Karachi, Pakistan
Sobia Khan Nabeel Department of Physiology, Baqai Medical University, Karachi, Pakistan
Hina Faisal Department of Pathology, Sir Syed College of Medical Sciences for Girls, Karachi, Pakistan

DOI:

https://doi.org/10.54393/pjhs.v6i9.3455

Keywords:

TLR7, Epigenetics, DNA Methylation, Post-COVID Syndrome, Immune Dysregulation, Type I Interferon

Abstract

Toll-like receptor 7 (TLR7) is crucial for recognizing single-stranded viral RNA and initiating type I interferon signalling, which initiates antiviral immune responses. DNA methylation and other epigenetic controls may affect TLR7 expression and play a role in immune dysregulation in post-COVID syndrome. Objectives: To assess the association between immune dysregulation in people with post-COVID syndrome and epigenetic regulation of the TLR7 gene, specifically DNA methylation patterns. Methods: Patients with post-COVID-19 symptoms (≥12 weeks’ post-infection) and age- and sex-matched recovered controls participated in a case-control study. The purpose of peripheral blood mononuclear cells (PBMCs) was to use bisulfite pyrosequencing to analyze the DNA methylation of TLR7 promoter CpG sites, to use qRT-PCR to quantify TLR7 mRNA, and to use flow cytometry to immunophenotype immune cell subsets and type I interferon (IFN-α) production. Analysis was done on statistical relationships among immune parameters, gene expression, and methylation status. Results: In comparison to controls, post-COVID patients showed notable changes in TLR7 promoter methylation patterns, with site-specific hypo- and hyper-methylation associated with corresponding changes in TLR7 expression. Anomalies in B-cell and plasmacytoid dendritic cell (pDC) profiles and dysregulated IFN-α levels were linked to aberrant expression, suggesting persistent innate immune activation. Conclusions: TLR7 epigenetic changes could be a factor in post-COVID-19 persistent immunological dysregulation. These results emphasize TLR7 methylation as a possible therapeutic target and biomarker. To confirm these correlations, more long-term research is needed.

References

Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS et al. Post-Acute COVID-19 Syndrome. Nature Medicine. 2021 Apr; 27(4): 601-15. doi: 10.1038/s41591-021-01283-z. DOI: https://doi.org/10.1038/s41591-021-01283-z

Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y et al. Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact. E-Clinical Medicine. 2021 Aug; 38. doi: 10.1016/j.eclinm.2021.101019. DOI: https://doi.org/10.1016/j.eclinm.2021.101019

Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC et al. Attributes and Predictors of Long COVID. Nature Medicine. 2021 Apr; 27(4): 626-31. doi: 10.1038/s41591-021-01292-y. DOI: https://doi.org/10.1038/s41591-021-01292-y

Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CM, Patel SK et al. Immunological Dysfunction Persists for 8 Months Following Initial Mild-to-Moderate SARS-CoV-2 Infection. Nature Immunology. 2022 Feb; 23(2): 210-6. doi: 10.1038/s41590-021-01113-x. DOI: https://doi.org/10.1038/s41590-021-01113-x

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 Mar; 185(5): 881-95.

Abrashev H, Abrasheva D, Nikolov N, Ananiev J, Georgieva E. A Systematic Review of Endothelial Dysfunction in Chronic Venous Disease—Inflammation, Oxidative Stress, and Shear Stress. International Journal of Molecular Sciences. 2025 Apr; 26(8): 3660. doi: 10.3390/ijms26083660. DOI: https://doi.org/10.3390/ijms26083660

Manik M andSingh RK. Role of Toll‐Like Receptors in Modulation of Cytokine Storm Signaling in SARS‐CoV‐2‐Induced COVID‐19. Journal of Medical Virology. 2022 Mar;94(3):869-77. doi: 10.1002/jmv.27405. DOI: https://doi.org/10.1002/jmv.27405

Constantin T, Pék T, Horváth Z, Garan D, Szabó AJ. Multisystem Inflammatory Syndrome in Children (MIS-C): Implications for Long COVID. Inflammopharmacology. 2023 Jul; 31(5): 2221. doi: 10.1007/s10787-023-01272-3. DOI: https://doi.org/10.1007/s10787-023-01272-3

Van Der Made CI, Simons A, Schuurs-Hoeijmakers J, Van Den Heuvel G, Mantere T, Kersten S et al. Presence of Genetic Variants among Young Men with Severe COVID-19. Journal of the American Medical Association. 2020 Aug; 324(7): 663-73. doi: 10.1001/jama.2020.13719. DOI: https://doi.org/10.1001/jama.2020.13719

Al Aboud NM, Tupper C, Jialal I. Genetics, Epigenetic Mechanism. 2023 Aug.

Loaeza-Loaeza J, Beltran AS, Hernández-Sotelo D. DNMTs and Impact of CpG Content, Transcription Factors, Consensus Motifs, LncRNAs, and Histone Marks on DNA Methylation. Genes. 2020 Nov; 11(11): 1336. doi: 10.3390/genes11111336. DOI: https://doi.org/10.3390/genes11111336

Janssen SM and Lorincz MC. Interplay Between Chromatin Marks in Development and Disease. Nature Reviews Genetics. 2022 Mar; 23(3): 137-53. doi: 10.1038/s41576-021-00416-x. DOI: https://doi.org/10.1038/s41576-021-00416-x

Corley MJ, Pang AP, Dody K, Mudd PA, Patterson BK, Seethamraju H et al. Genome-Wide DNA Methylation Profiling of Peripheral Blood Reveals an Epigenetic Signature Associated with Severe COVID-19. Journal of Leukocyte Biology. 2021 Jul; 110(1): 21-6. doi: 10.1002/JLB.5HI0720-466R. DOI: https://doi.org/10.1002/JLB.5HI0720-466R

De Moura MC, Davalos V, Planas-Serra L, Alvarez-Errico D, Arribas C, Ruiz M et al. Epigenome-Wide Association Study of Covid-19 Severity with Respiratory Failure. E-BioMedicine. 2021 Apr; 66. doi: 10.1016/j.ebiom.2021.103339. DOI: https://doi.org/10.1016/j.ebiom.2021.103339

He Z, Zhang R, Jiang F, Zhang H, Zhao A, Xu B et al. FADS1-FADS2 Genetic Polymorphisms Are Associated with Fatty Acid Metabolism Through Changes in DNA Methylation and Gene Expression. Clinical Epigenetics. 2018 Dec; 10(1): 113. doi: 10.1186/s13148-018-0545-5. DOI: https://doi.org/10.1186/s13148-018-0545-5

Angeloni A and Bogdanovic O. Enhancer DNA Methylation: Implications for Gene Regulation. Essays in Biochemistry. 2019 Dec; 63(6): 707-15. doi: 10.1042/EBC20190030. DOI: https://doi.org/10.1042/EBC20190030

Salvi V, Nguyen HO, Sozio F, Schioppa T, Gaudenzi C, Laffranchi M et al. SARS-CoV-2–Associated ssRNAs Activate Inflammation And Immunity Via TLR7/8. Journal of Clinical Investigation Insight. 2021 Sep; 6(18): e150542. doi: 10.1172/jci.insight.150542. DOI: https://doi.org/10.1172/jci.insight.150542

Gómez-Carballa A, Pardo-Seco J, Pischedda S, Rivero-Calle I, Butler-Laporte G, Richards JB et al. Sex-biased Expression of the TLR7 gene in Severe COVID-19 patients: Insights from transcriptomics and epigenomics. Environmental Research. 2022 Dec; 215: 114288. doi: 10.1016/j.envres.2022.114288. DOI: https://doi.org/10.1016/j.envres.2022.114288

Saksena N, Bonam SR, Miranda-Saksena M. Epigenetic Lens to Visualize the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) Infection in COVID-19 Pandemic. Frontiers in Genetics. 2021 Mar; 12: 581726. doi: 10.3389/fgene.2021.581726. DOI: https://doi.org/10.3389/fgene.2021.581726

Behura A, Naik L, Patel S, Das M, Kumar A, Mishra A et al. Involvement of epigenetics in Affecting Host Immunity During SARS-CoV-2 infection. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2023 Mar; 1869(3): 166634. doi: 10.1016/j.bbadis.2022.166634. DOI: https://doi.org/10.1016/j.bbadis.2022.166634

Calzari L, Dragani DF, Zanotti L, Inglese E, Danesi R, Cavagnola R et al. Epigenetic Patterns, Accelerated Biological Aging, and Enhanced Epigenetic Drift Detected 6 Months Following COVID-19 Infection: Insights from A Genome-Wide DNA Methylation Study. Clinical Epigenetics. 2024 Aug; 16(1): 112. doi: 10.1186/s13148-024-01764-1. DOI: https://doi.org/10.1186/s13148-024-01764-1