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Abstract
Background: In the fight against COVID-19, the use of an old anti-gout agent which is inexpensive and easily administered (1). A meta-analysis suggests a definite benefit with the addition of colchicine in patients with COVID-19(2). It was suggested that colchicine can have efficacy for hospitalized patients with a severe course of COVID-19 and concurrent inflammatory rheumatic diseases who have a higher risk of venous thromboembolism (3). On the other hand, some reports suggested that colchicine is associated with an increased risk of infections (4). Currently, there are nine clinical trials using colchicine for COVID-19(5), nevertheless, the exact mechanism of action is not well understood.
Objectives: Using publicly available transcriptomic data profiling human cells’ response to colchicine to identify core differentially expressed genes (DEGs) then examine the dynamics of the identified DEGs in different datasets of COVID-19 transcriptomics databases to suggest the possible mechanisms of action on the molecular level.
Methods: Gene Expression Omnibus was searched for human samples treated with colchicine compared to controls. GSE4090 dataset was identified where global gene expression of HUVEC (human umbilical vein endothelial cell line) cells exposed to various concentrations of colchicine (n=9) compared to controls (n=7). We reanalyzed this datset using GEO2R online tool to identify DEGs. The identified DEGs were searched in SARS-CoV-2 transcriptome datasets using metascape online tool to identify gene sets were the DEGs identified showed significant similarity.
Results: Fifty DEGs were identified in response to colchicine no matter what the concentration is used, (Figure 1A). Two gene sets (COVID323, RNA_Wilk_CD4+T-cells_patient-C2_Up [peripheral immune cells] and COVID008, RNA_Blanco-Melo_A549_Up[lung epithelial cells]) showed significant enrichment of the identified DEGs, (Figure 1B). SOCS3, ZC3H12C, CD55, GLIPR1, BACH1, PHLDA1, JUNB, NFKBIZ, and MYLIP were the shared genes between the identified DEGs, and the two gene sets with top enriched terms related to important immune-related pathways like IL-6, chemotaxis, leukocytes migration, cytokine release, and response to glucocorticoid, (Figure 1C). Only Suppressor of cytokine signaling 3 (SOCS3) was shared in the three datasets. SOCS3 expression was significantly downregulated in the HUVEC cells exposed to colchicine, (Figure 1D). Next, the normalized gene expression of SOCS3 from whole blood of 62 COVID-19 patients was compared to that of 24 healthy controls using (GSE15264) showed significant upregulation of SOCS3 in the blood of CVOID-19 patients indicating its role in COVID-19, (Figure 1E).
Conclusion: Our reanalysis showed that the possible beneficial effect of colchicine in COVID-19 patients might be through its direct effect on SOCS3 which is specifically upregulated in COVID-19 by IL6 and interferon (IFN)-gamma.
References: [1]Reyes AZ, Hu KA, Teperman J, Wampler Muskardin TL, Tardif J-C, Shah B, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Annals of the Rheumatic Diseases. 2020:annrheumdis-2020-219174.
[2]Vrachatis DA, Giannopoulos GV, Giotaki SG, Raisakis K, Kossyvakis C, Iliodromitis KE, et al. Impact of colchicine on mortality in patients with COVID-19. A meta-analysis. Hellenic Journal of Cardiology. 2021.
[3]Kow CS, Hasan SS. Colchicine as an adjunct to heparin for prophylaxis of venous thromboembolism in patients with COVID-19. Rheumatol Int. 2021:1-2.
[4]McEwan T, Robinson PC. A systematic review of the infectious complications of colchicine and the use of colchicine to treat infections. Semin Arthritis Rheum. 2020;51(1):101-12.
[5]Montealegre-Gómez G, Garavito E, Gómez-López A, Rojas-Villarraga A, Parra-Medina R. Colchicine: A potential therapeutic tool against COVID-19. Experience of 5 patients. Reumatología Clínica. 2020.
Disclosure of Interests: None declared.