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.

Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study

“…Few previous studies have investigated the role of MIP1b in COVID-19, although higher MIP1b in patients than controls has been observed (De Biasi et al, 2020;Hachim et al, 2020). This study showed internally consistent associations of MIP1b with COVID-19, indicating MIP1b may play a protective role in both COVID-19 vulnerability and hospitalization.…”

Hydroxychloroquine reduces T cells activation recall antigen responses

“…Our results are supported by a study from Goldman et al, showing that HCQ inhibited anti-TCR-induced-up-regulation of CD69 expression of CD4 + T cells [40] T cells expressing CCR5 have been suggested to play an important role in the rheumatoid arthritis pathology due to their capacity to migrate to inflamed synovium [42]. The capacity of HCQ treatment to decrease the expression of CCR5 was also observed in a study from Hachim et al [43]. Interestingly, CD4 + CD29 + T cells have been associated with the persistent inflammation observed in people with ulcerative colitis [44].…”

Computational identification of host genomic biomarkers highlighting their functions, pathways and regulators that influence SARS-CoV-2 infections and drug repurposing

“…The interleukin (IL) regulatory pathways are crucial for the important pathophysiological mechanisms called systemic inflammation and cytokine release syndrome [61][62][63] which were significantly associated with the hub genes (Supplementary File S1). The C-C chemokine binding functions driven by ZFP36 hub-DEG are directly involved with the T-cell induced pathogen burden controlling which is also an important receptor group protein for COVID-19 [63][64][65] . The NAD + nucleotidase MF (steered by TLR2 hub-DEG) was found to have protective roles, and mitigate the disease severity if administered prophylactically, and its anti-hyper inflammation properties 66,67 and the Dcp1-Dcp2 complex (steered by ZFP36 hub-DEG) play a positive role in viral infection 68 .…”

“…During this pandemic situation, the emergency COVID-19 positive patients were permitted to treat with the Hydroxychloroquine (HCQ) although its molecular mechanisms were not completely known and later on WHO advised to avoid this for the treatment. The HCQ -is also commonly used in rheumatic disease treatment and it has been shown that the patients with rheumatoid arthritis (RA) represent lower risk of COVID-19 infection 64 . In our analysis, the hub-DEGs TLR2 and CXCL2 significantly enriched the rheumatoid arthritis pathway which indicates that these genes may have the antagonized property against the COVID-19 infection.…”