An article recently published in the journal Frontiers in Immunology has described the role of cannabidiol, a phytochemical found in Cannabis sativa plants, as a potential inhibitor of hyperinflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The compound has been found to inhibit the production of several proinflammatory cytokines in SARS-CoV-2-infected cells.
Interaction between cannabidiol and viral proteins
The genome of SARS-CoV-2 encodes several viral proteins, including spike protein, viral main protease, RNA polymerase, and RNA-cleaving endoribonuclease. While the viral spike protein interacts with angiotensin converting enzyme 2 (ACE2) on the host cell membrane to initiate viral entry, the main protease is required to cleave viral polypeptides to generate several functional subunits required for viral replication.
Studies have shown that cannabidiol binds to SARS-CoV-2 main protease to block its transcription, which in turn inhibits viral replication. In addition, it binds to the CB2 receptor (type 2 cannabinoid receptor) and inhibits the secretion of proinflammatory macrophages in the lungs. Thus, cannabidiol can act as a potential antiviral and anti-inflammatory agent.
Cannabidiol and hyperinflammation in SARS-CoV-2 infection
Cannabidiol is known to inhibit the secretion of proinflammatory cytokines (IL-6 and TNF-alpha) by reducing the activity of inflammatory transcription factors, including AP-1 (activator protein 1, NFkB (nuclear factor kappa B), and NFAT (nuclear factor of activated T cells). In addition, cannabidiol has been found to induce interferon signaling during viral infection, leading to activation of the host immune system and early elimination of the virus.
Given the anti-inflammatory effects of cannabidiol, scientists have postulated that the compound can be used clinically to reduce hyperinflammation in coronavirus disease 2019 (COVID-19) patients. In SARS-CoV-2-infected lung fibroblast cells, cannabidiol has been found to suppress the secretion of several proinflammatory cytokines and chemokines, including COX-2, TNF-alpha, IL-6, and CCL2.
Cannabidiol as an antiviral agent in SARS-CoV-2 infection
Besides viral proteins, cannabidiol can directly act on certain host proteins responsible for viral entry, such as ACE2 and cellular protease TMPRSS2. Cannabidiol in combination with other phytochemicals, such as terpene and 7-hydrocannabidiol, has been found to suppress SARS-CoV-2 infection in both in vitro and in vivo studies.
Scientists have identified two possible modes of action of cannabidiol responsible for reducing hyperinflammation in COVID-19.
Cannabidiol and PPAR?
The one mode of action is the interaction of cannabidiol with peroxisome proliferator-activated receptor-gamma (PPAR?), which leads to downregulation of several proinflammatory mediators, including toll-like receptor 4 (TLR-4), family members of Ras homologues A-GTPase (RhoA-GTPase), inflammasome complex (NLRP3), and Caspase-1.
PPAR? is a transcription factor involved in many pathophysiological processes, including cell differentiation, protein and lipid metabolism, insulin sensitivity, neoplastic transformation, and inflammation. Activation of PPAR? in alveolar macrophages has been found to reduce inflammation, control cytokine secretion, prevent tissue damage, and increase host recovery process. Thus, cannabidiol as a PPAR? agonist can be used therapeutically to limit lung inflammation and fibrosis in COVID-19 patients.
Cannabidiol and WNT/ ?-catenin pathway
The other mode of action of cannabidiol might be through its interaction with PPAR? and WNT/ ?-catenin pathway. In SARS-CoV-2 infection, PPAR? and WNT/ ?-catenin pathways have been found to interact in an opposite manner. In sepsis-induced lung injury, upregulation of the WNT/ ?-catenin pathway occurs, leading to tissue fibrosis and inflammation. The stimulation of the WNT/ ?-catenin pathway by transforming growth factor (TGF-?) has been found to increase lung fibrosis and infection in COVID-19 patients.
In COVID-19, a crosstalk between ACE2 and WNT/ ?-catenin pathway has also been observed. An upregulation of ACE2 expression and WNT/ ?-catenin pathway signaling is associated with higher lung inflammation and tissue damage and a poor prognosis of COVID-19. In rat models of renal ischemia/reperfusion-induced injury, PPAR? agonists have shown beneficial effects by reducing ACE2 expression and WNT/ ?-catenin pathway signaling.
Taken together, it has been hypothesized in the study that cannabidiol can be used clinically to prevent hyperinflammation and lung tissue damage in COVID-19 patients. The activation of PPAR? by cannabidiol is hypothesized to be a possible mechanism of reducing ACE2 expression and WNT/ ?-catenin pathway signaling, which collectively could improve the clinical outcomes of COVID-19.
Studies investigating the therapeutic potential of cannabidiol in SARS-CoV-2 infection are at the preclinical level. Given the observed benefits, the scientists highlight the need for clinical trials to investigate the effectiveness of cannabidiol in routinely treating COVID-19 patients.