REVIEW
Can phytotherapy with polyphenols serve as a powerful approach for the
prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)?
Emile Levy,1,2,3,4 Edgard Delvin,1 Vale´rie Marcil,1,2,4 and Schohraya Spahis1,2,4
1Research Centre, Sainte-Justine University Health Center, Montreal, Quebec, Canada; 2Department of Nutrition, Universite´ de
Montre´al, Montreal, Quebec, Canada; 3Department of Pediatrics, Universite´ de Montre´al, Montreal, Quebec, Canada; and
4Institute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada
Submitted 12 June 2020; accepted in final form 1 August 2020
Levy E, Delvin E, Marcil V, Spahis S. Can phytotherapy with polyphenols
serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)? Am J Physiol Endocrinol Metab 319: E689–
E708, 2020. First published August 5, 2020; doi:10.1152/ajpendo.00298.2020.—
Much more serious than the previous severe acute respiratory syndrome (SARS)
coronavirus (CoV) outbreaks, the novel SARS-CoV-2 infection has spread speedily,
affecting 213 countries and causing 17,300,000 cases and 672,000 (+1,500/
day) deaths globally (as of July 31, 2020). The potentially fatal coronavirus disease
(COVID-19), caused by air droplets and airborne as the main transmission modes,
clearly induces a spectrum of respiratory clinical manifestations, but it also affects
the immune, gastrointestinal, hematological, nervous, and renal systems. The dramatic scale of disorders and complications arises from the inadequacy of current
treatments and absence of a vaccine and specific anti-COVID-19 drugs to suppress
viral replication, inflammation, and additional pathogenic conditions. This highlights the importance of understanding the SARS-CoV-2 mechanisms of actions
and the urgent need of prospecting for new or alternative treatment options. The
main objective of the present review is to discuss the challenging issue relative to
the clinical utility of plants-derived polyphenols in fighting viral infections. Not
only is the strong capacity of polyphenols highlighted in magnifying health benefits, but the underlying mechanisms are also stressed. Finally, emphasis is placed
on the potential ability of polyphenols to combat SARS-CoV-2 infection via the
regulation of its molecular targets of human cellular binding and replication, as
well as through the resulting host inflammation, oxidative stress, and signaling
pathways.
complications; microbiota; oxidative stress; polyphenols; viral infection
In view of the paucity of therapeutic findings and scantiness
of related mechanisms, it is surprising that polyphenolic compounds have not been tested to combat viral activities. However,
it is worth noting that, in addition to their antioxidative and antiinflammatory characteristics, polyphenols exhibit anti-infective
properties (220). Indeed, in the last two decades, numerous benefits of polyphenols against diverse families of viruses were suggested, as these safe and reliable nutrients displayed the capacity
to interrupt the life cycle of viruses and halt viral replication,
boost immune responses, and protect against inflammation in
infected patients. In the following sections, polyphenol properties, potential impact on various harmful viruses, and underlying
molecular mechanisms will be discussed before their application
in managing COVID-19 infection is proposed (Fig. 4)
POLYPHENOLS AND VIRAL INFLAMMATION
Following viral infection, it is possible to observe dysregulated host immune response and production of inflammatory
cytokines. COVID-19 patients exhibit elevated concentrations
of plasma IL2, IL6, IL7, IL10, granulocyte colony-stimulating
factor (GCSF), IFN-g-induced protein 10 (IP-10), monocyte
chemoattractant protein 1 (MCP1), macrophage inflammatory
protein 1-a (MIP1A), and TNFa (37, 101), indicating an
increased output of inflammatory components. With increasing
state of severity, NK and T cells run through, and the decline of
their number leads to lymphopenia. In compensation and for
continuing the fight against SARS-CoV-2 infection, the immune
system is hyper-stimulated to produce a profusion of cytokines
tapping highs, named “cytokine storm,” leading immune cells to
affect healthy tissues and cause organ failure (1). Remarkably,
polyphenols are known for their ability to prevent and counteract inflammation (Fig. 5) by mitigating inflammatory response
in adipocytes, macrophages, and additional immune cells (129).
As a polyphenolic phytochemical, curcumin can modulate dendritic cells (DCs) and transform them into tolerogenic DCs with anti-inflammatory and immunomodulatory activities in health
and disease (174). Accordingly, curcumin impedes the maturation and migration of cytokines and chemokines while disturbing
the antigen-presenting machinery of DCs, rendering them non- or
hyporesponsive to immunostimulants (80). These alterations may
be due to the downregulation of transcription factors, including
NF-κB, AP-1, MAPKs (p38, JNK, ERK), and other intracellular
signaling molecules such as JAK/STAT/SOCS (171). Similarly,
polyphenols from tea such as the bioactive EGCG could repress
the biogenesis of blood angiotensin II-associated C-reactive protein, which plays a vital role in the progression of inflammation
characterizing metabolic syndrome, atherosclerosis, and hepatic
diseases through the angiotensin II type 1 receptor-ROS-ERK1/2
signaling pathway (246), the modulation of Notch pathway in
human macrophages (227), and the upregulation of E3 ubiquitin
ligase RNF 216, followed by downregulation of toll-like receptor
4 (125). As we can therefore infer from these brief examples and
a multitude of others available in the scientific literature, polyphenols may not only be applied as antiviral tools, but also as powerful anti-inflammatory a gents capable of boosting antiviral
response POLYPHENOLS AND VIRAL OXIDATIVE STRESS
A molecular link is apparent between viral infection and OxS
pathways (16). For instance, OxS has been induced by the respiratory syncytial virus as reflected by raised NADPH oxidase-1,
an enzyme implicated in the formation of ROS, and declined endogenous antioxidant defense (e.g., catalase, glutathione Stransferase A2), likely resulting from downregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2), a strong transcription
factor undergoing histone deacetylation and proteasomal degradation
(120). The administration of antioxidants reduced ROS generation
and simultaneously lessened pulmonary inflammation and lung pathologies associated with respiratory syncytial virus infection, pointing
out OxS as a causal agent (7). Accordingly, lowering NADPH
oxidase 2 expression prevents NF-κB activation in respiratory syncytial virus in infected cells and drastically counteracts the induction
proinflammatory cytokines and chemokines (72). Other respiratory
viral infections (influenza, human metapneumovirus, parainfluenza,
adenovirus, CoV, and human rhinovirus) are also associated with redox imbalance/OxS and antioxidant mechanism slackness, highly
necessary for viral infection and complications (49). For their part,
SARS-CoVs trigger OxS mechanisms, which contribute to the
pathogenesis and progression of respiratory diseases (121). The
abundant ROS production, as a result of increased inflammatory cell
recruitment at the site of viral infection, is coupled with innate immunity and SARS-CoV 3CLpro-mediated NF-κB activation, leading
to an intensified proinflammatory host response (136). Clearly, it
was shown that OxS-NF-κB-toll-like receptor (mainly TLR4) signaling pathways are elicited by SARS-CoV to magnify host inflammatory response, thus contributing to acute lung injury. Such
abnormalities can be prevented by the intake polyphenols, known as
influential antioxidants capable of halting virus-driven ROS production and protecting host cells from OxS and the vicious inflammation
cycle (Fig. 5). By strengthening the antioxidant capacity and scavenging ROS, polyphenols may therefore represent a promising tool
to stop the negative effects of SARS-CoV-2 while ameliorating the
clinical course of COVID-19.
SUMMARY POINTS
1. The potential mechanisms for SARS-CoV-2 adhesion, entry,
and replication into host cells, along with multiple related complications, have been emphasized to prospect and design treatment options.
2. Given the lack of vaccine and effective antiviral agents for
COVID-19, evidence is provided to propose that natural polyphenolic compounds may serve as a useful arsenal to mitigate
coronaviral infection in view of their established beneficial
properties and functions.
3. The effectiveness of polyphenols has been first substantiated by
their powerful antiviral activities, as reflected by the modulation of viral envelope proteins (namely Spike S glycoprotein
instrumental for the specificity and infectivity of the virion) and
host cell receptors (e.g., ACE2 functioning as a gate for SARSCoV-2) and transmembrane proteases (e.g., TMPRSS2 mediating SARS-CoV-2 cell invasion).
4. As amply supported by the scientific literature, polyphenols are
endowed with the redoubtable antioxidant and anti-inflammatory actions capable of counteracting redox imbalance and
inflammatory processes elicited by SARS-CoV-2 infection and
accounting for enhanced patients’ susceptibility to severe organ
insults.
. A plethora of evidence underlines the favorable regulation of
microbiota by polyphenols, which may both amend dysbiosis
triggered by invading SARS-CoV-2 and boost antiviral
response, thereby turning down viral infectivity.
6. Bioactive polyphenols are known to improve cardiometabolic
health and alleviate the constellation of the risk factors associated with the metabolic syndrome (e.g., dyslipidemia, insulin
resistance, hypertension, and obesity), which would be most
helpful for preexisting cardiometabolic ailments displaying
poorer prognosis for the COVID-19 course.
CONCLUSIONS
The speed and severity of the present, deadly COVID-19 pandemic took the whole world by surprise. It has caused widespread woefulness, fear, anxiety, loneliness, and economic
uncertainty. This crisis is challenging health systems worldwide,
forcing countries to make difficult choices, mainly because of
the lack of a vaccine and effective standard treatment. In recognition of the seriousness of the SARS-CoV-2 strike and the urgency to limit the virus spread, polyphenols represent a valuable
therapeutic strategy for the management of SARS-CoV-2-
infected patients. Overall, from available evidence documented
by the present review, polyphenols are endowed with multifaceted beneficial properties. Their antiviral, antioxidant, antiinflammatory, antiobesogenic, antidiabetic, antithrombotic, and
prebiotic effects can be put in use to combat COVID-19. At
least, their potency must be tested given their ability to modulate
the different molecular, metabolic, and clinical targets of
SARS-CoV-2. Thorough investigation will allow for the definition of whether they may act synergistically with existing drugs
against the viral infection and related complications
