C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis

Abstract

Patients with rheumatoid arthritis (RA) represent one of the fragile patient groups that might be susceptible to the critical form of the coronavirus disease - 19 (COVID-19). On the other side, RA patients have been found not to have an increased risk of COVID-19 infection. Moreover, some of the Disease-Modifying Anti-Rheumatic Drugs (DMARDS) commonly used to treat rheumatic diseases like Hydroxychloroquine (HCQ) were proposed as a potential therapy for COVID-19 with a lack of full understanding of their molecular mechanisms. This highlights the need for the discovery of common pathways that may link both diseases at the molecular side. In this research, we used the in silico approach to investigate the transcriptomic profile of RA synovium to identify shared molecular pathways with that of severe acute respiratory syndrome-corona virus-2 (SARS-COV-2) infected lung tissue. Our results showed upregulation of chemotactic factors, including CCL4, CCL8, and CCL11, that all shared CCR5 as their receptor, as a common derangement observed in both diseases; RA and COVID-19. Moreover, our results also highlighted a possible mechanism through which HCQ, which can be used as a monotherapy in mild RA or as one of the triple-DMARDs therapy (tDMARDs; methotrexate, sulphasalazine, and HCQ), might interfere with the COVID-19 infection. This might be achieved through the ability of HCQ to upregulate specific immune cell populations like activated natural killer (NK) cells, which were found to be significantly reduced in COVID-19 infection. In addition to its ability to block CCR5 rich immune cell recruitment that also was upregulated in the SARS-COV-2 infected lungs. This might explain some of the reports that showed beneficial effects.

Fig. 1

Comparison between the synovium transcriptomics profile of rheumatoid arthritis (RA) patients versus healthy controls (N) and osteoarthritis (OA). a principle component analysis (PCA) showing that the top selected DEGs can cluster the groups precisely b Heatmap of the top markers that can differentiate the three groups and c shows top pathways enriched in RA specific markers identified

Fig. 2

Estimating immune cells infiltration in the synovium using transcriptomics profile of rheumatoid arthritis (RA) patients versus healthy controls (N) and osteoarthritis (OA). We used the ESTIMATE tool to estimate the difference in the infiltration of immune cells in healthy, OA, and RA synovium using their transcriptomic profile. The raw RNAseq data were used for in silico prediction of the immune cells’ infiltration of the synovial tissue using CIBERSORT analytical tool to evaluate changes in the immune population and/or activation status between the groups

Fig. 3

Flowchart for identification of DEGs between SARS-CoV-2 infected and uninfected lung samples using RNAseq dataset (GSE147507) retrieved from GEO using BioJupies tools. The flow of transcriptomics reanalysis, identification of chemokines, their common receptors, and immune cells with high receptor are summarized

Fig. 4

Effect of tDMARDs Treatment In Early RA synovial immune cells profile. We used the publicly available synovial tissue transcriptomic data to compare the infiltration of the immune cells at baseline and after six months of tDMARDs to identify subgroups that might not respond well to tDMARDs. RNAseq dataset (GSE97165) of synovial biopsies taken from 19 early RA (defined as within 12 months of the onset of symptoms) patients at baseline and after six months of tDMARDs treatment were retrieved and reanalyzed. ANOVA test was used

Fig. 5

CCR5 expression in synovial biopsies of RA and control and CCR5 expression at baseline and after six months of tDMARDs treatment. The expression of the chemokine receptor was searched in a microarray dataset (GSE77298) of synovial biopsies of RA and healthy controls. A paired T-test was used for comparison

Fig. 6

A working hypothesis for tDMARDs and COVID-19 interactions. The possible role of (1) SARS-COV-2 infected lungs (2) chemokines in recruiting (3) CCR5 rich immune cells. Epithelial cells secrete three chemokines that recruit immune cells that stimulate Th17 and Th1 profile to kill the virus but recruit inflammatory to the area. Infected epithelium can stimulate (4) plasma cells to secrete antiviral Ab that can (5) stimulate local macrophages to have an inflammatory M1 profile. tDMARDs can be helpful in the COVID-19 scenario by blocking CCR5 expression on immune cells plus inhibiting plasma amd M1 macrophages while enhancing NK cells to kill the virus