In a recently published article in the journal Frontiers in Immunology, scientists have reviewed the existing literature on antiviral and anti-inflammatory efficacy of resveratrol-based inhaled formulations in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reducing coronavirus disease 2019 (COVID-19) severity.
Background
SARS-CoV-2, the causative pathogen of COVID-19, is an enveloped, positive-sense, single-stranded RNA virus with a genome size of about 30kb. Being a respiratory virus, SARS-CoV-2 primarily attacks the upper respiratory tract and causes mild respiratory complications. If this remains unresolved, the virus can spread to the lower respiratory tract and cause viral pneumonia. In severe cases, an excessively high inflammatory microenvironment (cytokine storm) together with viral pneumonia can result in respiratory failure and death.
Therapeutic benefits of resveratrol
Resveratrol is a polyphenolic compound produced in various plants. This bioactive compound possesses many health benefits, including antimicrobial, antioxidant, anti-inflammatory, and anticancer activities. There is ample evidence indicating the therapeutic benefits of resveratrol in type 2 diabetes, neurological and cardiovascular diseases, and liver, breast, colorectal, pancreatic, and prostate cancers. Moreover, studies have pointed out the antiviral efficacy of resveratrol against respiratory viruses.
Antiviral efficacy of resveratrol
Resveratrol is known to limit viral replication by inhibiting viral gene expression and protein synthesis and downregulating various signaling pathways in cells. By reducing viral replication, resveratrol subsequently prevents heightened inflammatory responses, leading to the prevention of lung injuries. The antiviral potency of resveratrol has been documented against influenza A virus, respiratory syncytial virus, human rhinovirus, and middle east respiratory syndrome coronavirus (MERS-CoV).
Anti-SARS-CoV-2 efficacy of resveratrol
Studies investigating the anti-SARS-CoV-2 activity of resveratrol reveal that the compound significantly inhibits viral replication in host cells at low micromolar concentrations. About 98% reduction in replication can be achieved by treating the cells with resveratrol after viral entry. However, pretreatment of cells with resveratrol has been found to cause a very low level of inhibition. Interestingly, some studies have shown that treatment of cells with resveratrol during viral entry can cause more than 60% reduction in viral replication, indicating that the compound has some effect on viral entry into host cells. Overall, these observations suggest that resveratrol interferes with the viral life-cycle at the early phase of infection.
Apart from direct antiviral activities, resveratrol has been found to inhibit several pathogenic pathways associated with COVID-19. These include dysregulated NLRP3 inflammasome activation, renin-angiotensin system dysfunction, and kinin−kallikrein system stimulation.
NLRP3 inflammasome and autophagy
Under physiological conditions, pathogen-induced activation of NLRP3 inflammasome leads to the production of inflammatory cytokines, which in turn facilitate the induction of adaptive immunity against the pathogen. However, an aberrant dysregulated activation of NLRP3 inflammasome can lead to the development of inflammatory disorders.
In COVID-19, SARS-CoV-2-induced inhibition of cellular autophagy and excessive production of IL-1 beta has been found to cause uncontrolled activation of NLRP3 inflammasome. Resveratrol, on the other hand, can prevent dysregulated NLRP3 inflammasome activation by inducing SIRT1 (a deacetylase) activity, promoting autophagy, and reducing inflammation.
Angiotensin converting enzyme 2 and the renin-angiotensin system
Angiotensin-converting enzyme 2 (ACE2), a component of the renin-angiotensin system, is the primary host cell protein that facilitates SARS-CoV-2 entry. However, after host cell entry, SARS-CoV-2 downregulates the expression and activity of ACE2, leading to abnormal functioning of the renin-angiotensin system and excessive production of proinflammatory and prooxidant mediators. Collectively, these events lead to the development of alveolar edema and acute lung injury. In this context, it has been hypothesized that by inhibiting SARS-CoV-2 replication, resveratrol may restore physiological functions of the renin-angiotensin system and reduce lung inflammation.
ACE2 and the Kinin−Kallikrein System
ACE2 acts on the Kinin−Kallikrein System by producing bradykinin and its metabolites. SARS-CoV-2-mediated reduction in ACE2 expression can lead to dysregulation in the Kinin−Kallikrein System and induction in the lung inflammatory microenvironment. Excessive inflammation can subsequently make the lung vasculature more susceptible to leakage and angioedema formation.
Although no direct evidence is available regarding the effect of resveratrol in inducing ACE2 expression in SARS-CoV-2-infected cells, there are studies supporting the hypothesis that resveratrol can serve as a potent adjunct anti-inflammatory agent in COVID-19 by inhibiting bradykinin-induced COX-2/PGE2 production.
Resveratrol bioavailability
Despite having potent antiviral activity, resveratrol is not a clinically suitable compound because of poor stability in aqueous solutions and low bioavailability. After oral administration, resveratrol is rapidly absorbed and extensively metabolized in the intestine and liver. As a result, only trace amounts of unaltered resveratrol remain in the plasma for biological activities.
To prevent SARS-CoV-2 infection at the early stage, a high concentration of resveratrol in the airways can be achieved by topically administering the compound through inhaled formulations. In clinical trials, a nasal spray formulation comprising carboxymethylated glycan and resveratrol has shown good efficacy in reducing the severity and recurrence of upper respiratory tract infections of viral origin. It has been suggested that the nasal spray formulation provides antiviral protection mainly by upregulating toll-like receptor 2 (TLR2) expression.
Since SARS-CoV-2 primarily transmits via respiratory droplets and attacks nasal epithelial cells, complete control over infection can be achieved by inhibiting the viral replication in the upper respiratory tract and restricting the viral propagation in the lower respiratory tract. In this context, it is highly important to conduct clinical trials to investigate the antiviral efficacy of carboxymethylated glycan and resveratrol-based nasal formulation in treating acute SARS-CoV-2 infection in COVID-19 patients.
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