IDENTIFYING COMMON PROTEIN TARGET FOR COVID-19 AND EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS USING NETWORK ANALYSIS
DOI:
https://doi.org/10.53555/0dz66a57Keywords:
Coronavirus Disease 2019 , SARS-CoV-2 , GeneCards, DisGeNET, Gene Ontology , NF-κBAbstract
Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2 infection and a rare autoimmune disorder Eosinophilic Granulomatosis with Polyangiitis (EGPA) share key immune dysregulation mechanisms despite their distinct pathologies. This study uncovers the relationship between genes involved in COVID-19 and EGPA by network analysis approach to identify common potential therapeutic targets for the conditions . By comparing disease-associated genes retrieved from databases CTD, GeneCards and DisGeNET, 154 common genes expressed in both the disease conditions were identified. Protein-Protein Interaction network analysis revealed 10 hub proteins, which are central to immune responses, inflammation, and cytokine signaling pathways. Functional enrichment analyses of these genes using databases Gene Ontology (GO), KEGG, and Reactome, highlight shared pathways such as IL-6 and TNF signaling, which are critical in both diseases. Transcription factor network analysis pinpointed NF-κB as a central regulator of inflammatory responses. This research underscores the interconnectedness of COVID-19 and EGPA, emphasizing potential therapeutic targets like NF-κB for managing inflammation and disease progression in both conditions.
References
1. Mallah, S. I., Ghorab, O. K., Al-Salmi, S., Abdellatif, O. S., Tharmaratnam, T., Iskandar, M. A., Sefen, J. A. N., Sidhu, P., Atallah, B., El-Lababidi, R., & Al-Qahtani, M. (2021). COVID-19: Breaking down a global health crisis. Annals of Clinical Microbiology and Antimicrobials, 20, 35.
2. Shah, R. D., & Wunderink, R. G. (2017). Viral Pneumonia and Acute Respiratory Distress Syndrome. Clinics in Chest Medicine, 38(1), 113–125.
3. Nguyen, Y., & Guillevin, L. (2018). Eosinophilic Granulomatosis with Polyangiitis (Churg–Strauss). Seminars in Respiratory and Critical Care Medicine, 39, 471–481.
4. Santos, Y. A. P., Silva, B. R. A., Lira, P. N. Z. B. A., Vaz, L. C. A., Mafort, T. T., Bruno, L. P., & Lopes, A. J. (2017). Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) as a differential diagnosis of hypereosinophilic syndromes. Respiratory Medicine Case Reports, 21, 1–6.
5. Chakraborty, R. K., & Aeddula, N. R. (2024). Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome). In StatPearls. StatPearls Publishing.
6. Özdemir, B., Erden, A., Güven, S. C., Armagan, B., Apaydin, H., Karakas, Ö., Akdag, A. G., Ates, İ., Kucuksahin, O., & Omma, A. (2021). COVID-19 and eosinophilic granulomatosis with polyangiitis or COVID-19 mimicking eosinophilic granulomatosis with polyangiitis? Rheumatology International, 41(8), 1515.
7. Antovic, A., Lövström, B., Hugelius, A., Borjesson, O., Bruchfeld, A., & Gunnarsson, I. (2021). Pos1230 Outcome Following Covid-19 Infection in Anti-Neutrophil Cytoplasmic Antibody (anca)-Associated Vasculitis. Annals of the Rheumatic Diseases, 80(Suppl 1), 898–898
8. Fijolek, J., & Radzikowska, E. (2023). Eosinophilic granulomatosis with polyangiitis – Advances in pathogenesis, diagnosis, and treatment. Frontiers in Medicine, 10, 1145257.
9. Polak, S. B., Van Gool, I. C., Cohen, D., von der Thüsen, J. H., & van Paassen, J. (2020). A systematic review of pathological findings in COVID-19: A pathophysiological timeline and possible mechanisms of disease progression. Modern Pathology, 33(11), 2128–2138.
10. Daniel, P., Raad, M., Waked, R., Choucair, J., Riachy, M., & Haddad, F. (2020). COVID-19 in a Patient Treated for Granulomatosis with Polyangiitis: Persistent Viral 32 Shedding with No Cytokine Storm. European Journal of Case Reports in Internal Medicine.
11. Fliesler, N. (2022, April 6). How COVID-19 triggers massive inflammation. Boston Children’s Answers. https://answers.childrenshospital.org/covid-19-inflammation/
12. Davis, A. P., Grondin, C. J., Johnson, R. J., Sciaky, D., Wiegers, J., Wiegers, T. C., & Mattingly, C. J. (2021). Comparative Toxicogenomics Database (CTD): Update 2021. Nucleic Acids Research, 49(D1), D1138–D1143
13. Safran, M., Rosen, N., Twik, M., BarShir, R., Stein, T. I., Dahary, D., Fishilevich, S., & Lancet, D. (2021). The GeneCards Suite. In I. Abugessaisa & T. Kasukawa (Eds.), Practical Guide to Life Science Databases (pp. 27–56). Springer Nature.
14. C, Juan Manuel Ramírez-Anguita, Josep Saüch-Pitarch, & Francesco Ronzano. (n.d.). DisGeNET knowledge platform for disease genomics: 2019 update | Nucleic Acids Research | Oxford Academic. Retrieved April 22, 2024
15. Szklarczyk, D., Gable, A. L., Nastou, K. C., Lyon, D., Kirsch, R., Pyysalo, S., Doncheva, N. T., Legeay, M., Fang, T., Bork, P., Jensen, L. J., & von Mering, C. (2021). The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Research, 49(D1), D605–D612.
16. Otasek, D., Morris, J. H., Bouças, J., Pico, A. R., & Demchak, B. (2019). Cytoscape Automation: Empowering workflow-based network analysis. Genome Biology, 20(1), 185.
17. Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Research, 13(11), 2498–2504.
18. Cline, M. S., Smoot, M., Cerami, E., Kuchinsky, A., Landys, N., Workman, C., Christmas, R., Avila-Campilo, I., Creech, M., Gross, B., Hanspers, K., Isserlin, R., Kelley, R., Killcoyne, S., Lotia, S., Maere, S., Morris, J., Ono, K., Pavlovic, V., … Bader, G. D. (2007). Integration of biological networks and gene expression data using Cytoscape. Nature Protocols, 2(10), 2366–2382.
19. Kuleshov, M. V., Jones, M. R., Rouillard, A. D., Fernandez, N. F., Duan, Q., Wang, Z., Koplev, S., Jenkins, S. L., Jagodnik, K. M., Lachmann, A., McDermott, M. G., Monteiro, C. D., Gundersen, G. W., & Ma’ayan, A. (2016). Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Research, 44(W1), W90–W97.
20. Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., Davis, A. P., Dolinski, K., Dwight, S. S., Eppig, J. T., Harris, M. A., Hill, D. P., Issel-Tarver, L., Kasarskis, A., Lewis, S., Matese, J. C., Richardson, J. E., Ringwald, M., Rubin, G. M., & Sherlock, G. (2000). Gene Ontology: Tool for the unification of biology. Nature Genetics, 25(1), 25–29.
21. Kanehisa, M., Furumichi, M., Sato, Y., Ishiguro-Watanabe, M., & Tanabe, M. (2021). KEGG: Integrating viruses and cellular organisms. Nucleic Acids Research, 49(D1), D545–D551.
22. Martens, M., Ammar, A., Riutta, A., Waagmeester, A., Slenter, D. N., Hanspers, K., A. Miller, R., Digles, D., Lopes, E. N., Ehrhart, F., Dupuis, L. J., Winckers, L. A., Coort, S. L., Willighagen, E. L., Evelo, C. T., Pico, A. R., & Kutmon, M. (2021). WikiPathways: Connecting communities. Nucleic Acids Research, 49(D1), D613 D621
23. Jassal, B., Matthews, L., Viteri, G., Gong, C., Lorente, P., Fabregat, A., Sidiropoulos, K., Cook, J., Gillespie, M., Haw, R., Loney, F., May, B., Milacic, M., Rothfels, K., Sevilla, C., Shamovsky, V., Shorser, S., Varusai, T., Weiser, J., … D’Eustachio, P. (2020). The reactome pathway knowledgebase. Nucleic Acids Research, 48(D1), D498–D503.
24. Nishimura, D. (2001). BioCarta. Biotech Software & Internet Report, 2(3), 117–120.
25. Jiang, Y., Zhao, T., Zhou, X., Xiang, Y., Gutierrez‐Castrellon, P., & Ma, X. (2022). Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions. MedComm, 3(3), e154.
26. Zhou, G., Soufan, O., Ewald, J., Hancock, R. E. W., Basu, N., & Xia, J. (2019). NetworkAnalyst 3.0: A visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Research, 47(W1), W234–W241.
27. Tanaka, T., Narazaki, M., & Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspectives in Biology, 6(10), a016295.
28. Imai, Y., Kondo, Y., Ishigaki, S., Nishina, N., Ota, Y., Hanaoka, H., Kaneko, Y., & Takeuchi, T. (2022). A case of eosinophilic granulomatosis with polyangiitis after prolonged intervals of an anti-interleukin-6 receptor antibody for rheumatoid arthritis. Modern Rheumatology Case Reports, 6(1), 83–86.
29. Wang, X., Tang, G., Liu, Y., Zhang, L., Chen, B., Han, Y., Fu, Z., Wang, L., Hu, G., Ma, Q., Sheng, S., Wang, J., Hu, X., & Shao, S. (2022). The role of IL-6 in coronavirus, especially in COVID-19. Frontiers in Pharmacology, 13.
30. Gioffredi, A., Maritati, F., Oliva, E., & Buzio, C. (2014). Eosinophilic Granulomatosis with Polyangiitis: An Overview. Frontiers in Immunology, 5, 549.
31. Tanveer, A., Akhtar, B., Sharif, A., Saleem, U., Rasul, A., Ahmad, A., & Jilani, K. (2022). Pathogenic role of cytokines in COVID-19, its association with contributing co-morbidities and possible therapeutic regimens. Inflammopharmacology, 30(5), 1503.
32. Isozaki, T., Homma, T., Sagara, H., & Kasama, T. (2020). Role of Cytokines in EGPA and the Possibility of Treatment with an Anti-IL-5 Antibody. Journal of Clinical Medicine, 9(12), 3890.
33. Rabaan, A. A., Al-Ahmed, S. H., Muhammad, J., Khan, A., Sule, A. A., Tirupathi, R., Mutair, A. A., Alhumaid, S., Al-Omari, A., Dhawan, M., Tiwari, R., Sharun, K., Mohapatra, R. K., Mitra, S., Bilal, M., Alyami, S. A., Emran, T. B., Moni, M. A., & Dhama, K. (2021). Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm. Vaccines, 9(5), 436.
34. Fijolek, J., & Radzikowska, E. (2023). Eosinophilic granulomatosis with polyangiitis – Advances in pathogenesis, diagnosis, and treatment. Frontiers in Medicine, 10, 1145257.
35. Jahaj, E., Vassiliou, A. G., Keskinidou, C., Gallos, P., Vrettou, C. S., Tsipilis, S., Mastora, Z., Orfanos, S. E., Dimopoulou, I., & Kotanidou, A. (2021). Evaluating the Role of the Interleukin-23/17 Axis in Critically Ill COVID-19 Patients. Journal of Personalized Medicine, 11(9), 891.
36. Jiang, Y., Zhao, T., Zhou, X., Xiang, Y., Gutierrez‐Castrellon, P., & Ma, X. (2022). Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions. MedComm, 3(3), e154.
37. Hwang, S.-Y., Kim, J.-Y., Kim, K.-W., Park, M.-K., Moon, Y., Kim, W.-U., & Kim, H.-Y. (2004). IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways. Arthritis Research & Therapy, 6(2), R120–R128.
38. Lee, J., Wang, P., Kattah, M., Youssef, S., Steinman, L., Defea, K., & Straus, D. (2008). Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells. Journal of Immunology (Baltimore, Md. : 1950), 181, 6536–6545.
39. Rodriguez-Pla, A., Warner, R. L., Cuthbertson, D., Carette, S., Khalidi, N. A., Koening, C. L., Langford, C. A., McAlear, C. A., Moreland, L. W., Pagnoux, C., Seo, P., Specks, U., Sreih, A. G., Ytterberg, S. R., Johnson, K. J., Merkel, P. A., & Monach, P. A. (2020). Evaluation of Potential Serum Biomarkers of Disease Activity in Diverse Forms of Vasculitis. The Journal of Rheumatology, 47(7), 1001–1010.
40. Isozaki, T., Homma, T., Sagara, H., & Kasama, T. (2020). Role of Cytokines in EGPA and the Possibility of Treatment with an Anti-IL-5 Antibody. Journal of Clinical Medicine, 9(12), 3890.
41. Mohd Zawawi, Z., Kalyanasundram, J., Mohd Zain, R., Thayan, R., Basri, D. F., & Yap, W. B. (2023). Prospective Roles of Tumor Necrosis Factor-Alpha (TNF-α) in COVID-19: Prognosis, Therapeutic and Management. International Journal of Molecular Sciences, 24(7), 6142.
42. Todorović-Raković, N., & Whitfield, J. R. (2021). Between immunomodulation and immunotolerance: The role of IFNγ in SARS-CoV-2 disease. Cytokine, 146, 155637.
43. Kastenhuber, E. R., & Lowe, S. W. (2017). Putting p53 in Context. Cell, 170(6), 1062–1078.
44. Do, H., Ahn, S. S., Pyo, J. Y., Song, J. J., Park, Y.-B., & Lee, S.-W. (2022). Interferon gamma Release Assay Results Are Reliable for Screening for Latent Tuberculosis in Antineutrophil Cytoplasmic Antibody-associated Vasculitis. In Vivo, 36(6), 2884 2889.
45. Liu, T., Zhang, L., Joo, D., & Sun, S.-C. (2017). NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(1), 1–9.
