Can phytotherapy with polyphenols serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)?

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.

INTRODUCTION

Coronavirus disease-19 (n class="Disease">COVID-19) is a novel coronavirus originating from the city of Wuhan in China. With more than 213 countries and territories affected, the pandemic spread across the globe. So far, nearly 17,300,000 people have been infected worldwide and 672,000 have died (as of July 31, 2020). Although the main part of the pandemic passed in China, the viral crisis is now hitting many countries by infecting and killing thousands: 4,582,000/154,200 in the United States; 301,455/45,961 in the United Kingdom; 329,721/28,441 in Spain; 246,776/35,129 in Italy; 2,556,210/90,215 in Brazil; 185,196/30,238 in France; and 115,617/8,957 in Canada, to name a few. Everywhere, the healthcare system is facing a looming shortage of medical equipment, the residents are confined to their homes, the economy and financial markets are profoundly shaken, the usual consumption pattern is distorted, and the world panics (142, 144, 201).

Although governments have launched unprecedeene">nted public-health aene">nd econon class="Gene">mic responses, thousands of new cases are reported every day (201). The majority of people with mild symptoms recover on their own. Notably, it has been shown that high levels of the virus are present in respiratory secretions in asymptomatic subjects or during the “presymptomatic” period prior the development of the fever and cough, which are characteristic of COVID-19 (144). Moreover, many patients with COVID-19 display major complications and are hospitalized in intensive care units (77, 89, 206). Although there is no novel or proven therapy against COVID-19, patients are treated with antiviral drugs such as oseltamivir, ganciclovir, and remdesivir in the hopes of inhibiting SARS-CoV-2 replication (130). In view of the inflammatory cytokine storm highly present in patients with severe COVID-19 causing acute lung injury, anti-inflammatory medications are proposed. Although several governments and international health authorities have promoted and encouraged the treatment with chloroquine/hydroxychloroquine (71, 76, 128, 157), it must nonetheless be noted that these compounds present critical risk and benefit balance issues (44, 185, 216). In this context, recent clinical investigations have assessed promising alternatives, including chloroquine and its hydroxyl analog hydroxychloroquine, to evaluate whether they could prevent the virus from entering host cells, preclude viral replication, and dampen exacerbation of the immune response (44, 182, 185, 216). The findings did not reveal high-quality evidence to support these proposed aminoquinoline therapies (35, 74). Outcomes from large cohort trials are needed to definitely inform the international medical community about the proven clinical effectiveness.

Polyphenols are plaene">nt-derived n class="Chemical">phenolic compounds (Fig. 1) endowed with antioxidants and anti-inflammatory, immune, antitumor, and prebiotic properties. They show benefits for the prevention and treatment of a wide array of chronic diseases, such as insulin resistance, metabolic syndrome, type 2 diabetes (T2D), nonalcoholic fatty liver disease, and atherosclerosis (3–6, 51, 152, 155, 163, 175).

Fig. 1.

Main classes of polyphenols. Polyphenols are classified into flavonoids and nonflavonoids that contain a diverse group of compounds with a phenolic acid.

Main classes of n class="Chemical">polyphenols. Polyphenols are classified into flavonoids and nonflavonoids that contain a diverse group of compounds with a phenolic acid.

Healthful pharmacological properties were also observed in inflan class="Gene">mmatory pulmonary diseases in response to naturally occurring polyphenols (199, 215). Additionally, polyphenols disclose inhibitory activity against many viral components and actions (110, 165). Currently, there is no specific antiviral treatment or effective vaccine to control COVID-19; hence, there is an unmet need to determine whether alternative treatments offer improved efficacy. The objective of the present article is precisely to exhaustively analyze existing literature to evaluate the promising hypothesis regarding the potential of powerful polyphenols to fight COVID-19 infection while discussing related mechanisms through comparisons of their effects in other acute infectious diseases.

COVID-19 GENOME, PROTEIN STRUCTURE, AND LIFE CYCLE

SARS-CoV-2 is the seveene">nth ideene">ntified n class="Species">coronavirus (CoV) capable of infecting humans (232). As in the case of other CoVs, SARS-CoV-2 is pleomorphic or spherical with a particle size of 150–160 nm, containing positive single-stranded RNA, nucleoprotein, capsid, matrix, and S-protein (Fig. 2). More precisely, the characteristic viral proteins comprise envelope protein (E), nucleocapsid proteins (N), membrane glycoproteins (M), and spike glycoprotein (S) (167). Separately from other CoVs, SARS-CoV-2 displays an additional glycoprotein that has acetyl esterase and hemagglutination properties (117, 232). As per the typical genome organization of the -COVs, SARS-CoV-2 exhibits the 5′ untranslated region (UTR), S gene, E gene, M gene, N gene, 3′ UTR, and other open reading frames (ORFs). Recently, on the basis of various computational tools, ORF 1a and 1b of SARS-CoV-2 are fitted with ∼2/3 of the whole genome and code for 16 nonstructural proteins (nsp1‐16) (117). The −1 frameshift located between ORF1a and ORF1b regions imparts to the formation of pp1a and pp1ab polypeptides (164), which are further processed by viral-encoded proteases into 16 nsp. A section within the nsp2 and the nsp3, with no homology with other CoVs, may provide COVID-19 with the potency of infectiousness. The spike glycoprotein S is composed of two subunits S1 and S2, which mediate binding of COVID-19 (driven by S1) to its receptor and host cell membrane fusion (driven by S2) allowing virus entry (248). Host cell proteins contribute to viral S protein cleavage at the S1/S2 site [transmembrane protease serine 2 (TMPRSS2)] and cell attachment (ACE2 for angiotensin-converting enzyme 2), thereby leading to the merging of the viral capsid and cellular membrane. If presently the spike protein S is considered as the outermost component, which determines the host specificity and infectivity of the virion, the N protein is instrumental for the capsid development and the full viral structure (198). Additionally, the N terminal domain of the N protein binds to the viral (+) sense RNA, thus resulting in the CoV ribonucleoprotein complex, which is essential for the virus replication (181). With regard to the other proteins, the E moiety serves for the viral assembly and comprises ion channel actions (186), and the M protein also participates in the assembly of new virus particles (159). To initiate its life cycle and proficiently replicate for the production of progeny viruses, several processes (i.e., attachment, entry, induction of replicase proteins, replication, transcription, assembly, and discharge of mature viral particles) have to take place (Fig. 3). Following attachment of the virus to host cells via binding of the S1 region (C-terminus) to the receptor (ACE2, DPP4), the S protein is cleaved by host proteases (endosomal cathepsins, TMPRSS, furin, or trypsin) to be functional and activate fusogenicity, with an impact on tropism and pathogenicity (150). Thereafter, there is a fusion of the viral envelope with a host plasma membrane and acidified endosomes resulting in the release of the viral genome into the cytoplasm of the infected cell. The latter process is facilitated by the low pH of the endosomes and the S2 functional subunit of the S spike protein (17). It is at this stage that the SARS-CoV-2 takes advantage of the host endoplasmic reticulum (ER) to form numerous double membrane vesicles to shield viral genome and allow the replication to occur through the replication−transcription complex (85). Making use of the host cell protein translation machinery, the viral genome is translated into viral polyproteins, which are split into structural and nonstructural viral proteins by the viral proteases Mpro and PLpro (137). The assembly of viral particles (virions) is performed in the ER/Golgi compartment (48). Assembled virions are then carried to the cell surface, discharged from the cells through exocytosis, and proceed to infect other cells (Fig. 3).

Fig. 2.

Genomic organization and structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [created with BioRender.com]. The genome sequencing includes two large genes, open reading frame (ORF)1A and ORF1B, which encode 1–16 nonstructural proteins constituting a replication–transcription complex, closely involved in the genome transcription and replication. The structural genes encode the following structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). The additional accessory proteins are specific for SARS-CoV-2 in terms of number, genomic organization, sequence, and function. 3CLpro, 3-chymotrypsin-like protease; UTR, untranslated region.

Fig. 3.

Replication cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the target cell [created with BioRender.com]. The illustration details the replication cycle of the virus starting from binding of the S Spike to the receptor angiotensin-converting enzyme 2 (ACE2) and other potential receptors. Through endosomal membrane fusion, the virus enters the cell and releases its RNA genome. Following transcription and translation, the products (viral structural and nonstructural proteins and genomic RNA) are assembled into virions, transported by vesicles, and released out of the target cell.

Genomic orgaene">nization aene">nd structure of n class="Species">severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [created with BioRender.com]. The genome sequencing includes two large genes, open reading frame (ORF)1A and ORF1B, which encode 1–16 nonstructural proteins constituting a replication–transcription complex, closely involved in the genome transcription and replication. The structural genes encode the following structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). The additional accessory proteins are specific for SARS-CoV-2 in terms of number, genomic organization, sequence, and function. 3CLpro, 3-chymotrypsin-like protease; UTR, untranslated region.

Replication cycle of severe acute respiratory syndrome coronavirus 2 (n class="Species">SARS-CoV-2) in the target cell [created with BioRender.com]. The illustration details the replication cycle of the virus starting from binding of the S Spike to the receptor angiotensin-converting enzyme 2 (ACE2) and other potential receptors. Through endosomal membrane fusion, the virus enters the cell and releases its RNA genome. Following transcription and translation, the products (viral structural and nonstructural proteins and genomic RNA) are assembled into virions, transported by vesicles, and released out of the target cell.

COVID-19 SYMPTOMS

Following a 5-day incubation, the patients n class="Gene">may present with at least one of the symptoms such as fever, cough, breath shortness, sore throat, and fatigue, which represent the dominant symptoms of COVID-19 illness. However, many subjects also complain of headaches, hemoptysis, muscle soreness, diarrhea, and dyspnea. Subsequently, the patients may develop pneumonia, acute respiratory distress syndrome, acute cardiac problems, and multiorgan failure (184). The loss of sense of smell and taste has often been reported. Even if the coronavirus primarily targets the respiratory system, it has the potential to spread from the respiratory tract (through the olfactory bulb) to the central nervous system, causing inflammation and demyelination, with related complications (from confusion and headache to febrile seizures or encephalitis) (8, 53). Additionally, numerous hospitalized patients had underlying conditions, including obesity, hypertension, diabetes mellitus, and cardiovascular diseases. Clearly, the SARS-CoV-2 infection represents a challenge for physicians because no specific and effective drug is currently available for COVID-19, thereby posing a serious threat to human health.

ANTI-CORONAVIRUS THERAPEUTICS AND PROPHYLACTICS

From the outset, the abseene">nce of specific vaccine aene">nd aene">ntiviral ageene">nts n class="Gene">makes patient management difficult. The current pharmacotherapy refers to a broad-spectrum antiviral arsenal, which has been used to treat previous viral infections. Therefore, collecting hospitalization data and tracking clinical features and outcomes are mandatory to establish the clinical spectrum of COVID-19, which is instrumental to containing and managing this new pandemic.

Drugs formerly en class="Gene">mployed for SARS-CoV and Middle East respiratory syndrome-coronavirus (MERS-CoV) have been among the management options for COVID-19 pneumonia. In China, the antiretroviral drugs used for the human immunodeficiency virus (HIV) have also been considered, including lopinavir/ritonavir in combination with the anti-flu drug oseltamivir (45). Even remdesivir, known as a powerful agent to treat patients with Ebola virus, has been administered in the United States against COVID-19. Moreover, the antiviral and anti-inflammatory effects of antimalarial chloroquine and its derivatives (e.g., hydroxychloroquine) have been tested without success, and more studies are needed to prove the dose-response effectiveness (74, 182).

In view of the paucity of therapeutic findings and scantiness of related mechaene">nisn class="Gene">ms, 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 anti-inflammatory 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).

Fig. 4.

Potential cross-talk between gut microbiota and lungs during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [created with Servier Medical Art]. The gut–lung axis is bidirectional and able to induce changes in the blood and respective microbiota, illustrating the association of gut microbiota dysbiosis with local and distal pulmonary system. For example, the inflammation occurring in the pulmonary system leads to modifications in gut microbiota, and vice versa. LPS: Lipopolysaccharide.

Potential cross-talk betweeene">n n class="Gene">gut microbiota and lungs during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [created with Servier Medical Art]. The gut–lung axis is bidirectional and able to induce changes in the blood and respective microbiota, illustrating the association of gut microbiota dysbiosis with local and distal pulmonary system. For example, the inflammation occurring in the pulmonary system leads to modifications in gut microbiota, and vice versa. LPS: Lipopolysaccharide.

ANTIVIRAL ACTIVITIES OF POLYPHENOLS

Herpes Simplex Virus Type 1

Propolis is produced by bees aene">nd contains n class="Chemical">polyphenols, including flavonoids and phenylcarboxylic as major constituents (190). Preincubation of propolis extracts with African green monkey kidney cells (Vero cells) before infection with herpes simplex virus type 1 (HSV-1) strain KOS resulted in inhibition of >98% viral plaque formation (infectivity) and herpetic activity at maximum noncytotoxic concentrations in mice (196). Administration of propolis before or at the time of infection yielded the most significant inhibitory effect. Propolis extracts were proposed to interfere with HSV-1 attachment to cells via its surface structures and proteins, thereby blocking its adsorption and penetration into host cells (238). Contrary to acyclovir, propolis extracts do not inhibit viral DNA polymerase responsible for intracellular replication of HSV-1 in cell lines (238). In men and women, the administration of propolis was effective in respiratory tract infections (42) and genital herpes, respectively, hasting the healing process in the presence of acyclovir (223). The aforementioned observations highlight the promising actions of propolis polyphenol content, but additional efforts are still necessary to indicate whether propolis extracts directly cause virion damage. Validation of the propolis findings was obtained with almond skin polyphenols. These compounds hampered HSV-1 adsorption to Vero cells and restricted the virion inside the cells (20). Later, the same group demonstrated a radical drop of the HSV‐1 viral infectivity along with a significant decrease in the accumulation of viral proteins (e.g., ICP0 or UL42) and DNA in the standard American Type Culture Collection (ATCC) and clinical strains of Staphylococcus aureus (158), which prompts the use of polyphenol extracts for the development of novel virucide agents.

Resveratrol in class="Gene">mpact was assessed in HeLa, Vero, and HEK-293 T cells with respect to HSV-2 infection. Resveratrol was capable of stimulating histone acetylation and activation of NF-κB transcription factor, thereby releasing the chromatin structure from depressed condition and triggering HSV transcription (56). These data are not in accordance with previous investigations, which reported inhibition of HSV-1 and HSV-2 replication in human-lung cell lines (MRC-5) by resveratrol in a dose- and time-dependent manner (59). Resveratrol also exhibited a comparable efficient blockade of HSV replication like acyclovir in the vagina of mice (39). Differences in cell types and doses may explain the opposite data observed, which argues for clarification with additional studies.

Influenza Virus

Maene">ny types of berries display aene">ntiviral activities. Son class="Gene">me of them such as elderberry and blueberry are able to impede the replication in cell lines (104), which may relieve the symptoms of influenza virus. Several blueberry varieties exert anti‐influenza viral activities, especially viral adsorption, which positively correlated with the total polyphenol content in Madin-Darby canine kidney cells (192).

Resveratrol exhibited poteene">nt inhibitory effects against the n class="Species">influenza in MDCK cells via the blockade of nuclear-cytoplasmic translocation of viral ribonucleoprotein complexes, the decrease in the expression of late viral proteins, and the inhibition of cellular protein kinase C activity and its dependent pathways (162). In view of these observations, the authors proposed that resveratrol acts on posttranscriptional phases of the viral life cycle. Other studies were able to show the attenuation of replication of influenza A and H1N1 in A549 lung cancer cells, not only through stimulation of INF-through Toll-like receptor (TLR)9, but also via the downregulation of hemagglutinin (facilitating the binding of the virus to target cells) and neuraminidase (responsible for the cleavage of the host cellular receptors and release of the progeny virus) (135). On that basis, resveratrol may serve for the development of novel antiviral therapies against influenza provided that the data are validated in clinical trials.

Zika Virus

Resveratrol (3, 4′, 5-trihydroxystilbeene">ne), a natural n class="Chemical">polyphenolic compound found in the skins of red fruits, shows broad therapeutic benefits. Its effects were examined on Zika virus (ZIKV) belonging to the Flaviviridae family of the genus Flavivirus. At low concentrations (80 µM), resveratrol administration led to >90% inhibition without cytotoxicity to human hepatocellular carcinoma (Huh7) and Vero cells (153). Not only does resveratrol inhibit binding of ZIKV particles to cells, but it also reduces circulating ZIKV particles, which underlines its potential of limiting disease severity during the viraemic phase. Furthermore, the decline of ZIKV mRNA copy numbers in response to the resveratrol treatment suggests inhibitory effects against intracellular ZIKV replication.

Dengue Virus

Resveratrol exerts aene">n inhibitory effect on deene">ngue n class="Disease">infection, which is transmitted to humans by Aedes mosquitoes and threatens more than one-third of the world’s population, as 96 million individuals (particularly in children between 2 and 16 yr) seem to be affected annually (19). Despite the recently developed vaccine against dengue virus (DENV), the observations in two phase 3 trials with 30,000 children provide only partial efficacy (222), with ∼60% overall depending on the four serotypes (DENV1–4) (84). Therefore, various groups focused on resveratrol and its analogs (e.g., PNR-4-44 and PNR-5-02) to reveal anti-DENV activities, an initiative that has proven to be true (88). Subsequently, it turned out that resveratrol mediates the inhibitory effect on DENV by retaining the high-mobility group box 1 (HMGB1) in the nucleus of human hepatocellular carcinoma cells, thus preventing its migration to cytoplasm and binding to viral proteins to enhance viral replication (240). As a significant complement of information for this mechanism of action, resveratrol induces sirtuin (Sirt)1 synthesis to initiate HMGB1 deacetylation and retention of HMGB1 in the nucleus of various cell lines (102). Altogether, resveratrol may likely target factors or pathways inside host cells, contributing to anti-DENV activities, which will alleviate dengue symptoms ranging from mild fever to hemorrhagic fever and dengue shock syndrome.

Respiratory Syncytial Virus

Resveratrol was also tested in n class="Species">respiratory syncytial virus (RSV), characterized by persistent airway inflammation, airway hyperresponsiveness, and childhood recurrent wheezing and asthma (70). Resveratrol was able to lower the expression of Toll-like receptors-Toll/IL-1-receptor domain containing adaptor protein inducing IFN-β pathway in 9HTEo cells derived from human tracheal epithelium to block the formation of RSV-induced IFN-γ and IL-6, thereby ameliorating acute airway inflammation and airway hyperresponsiveness (138) via the suppression of nerve growth factor production in respiratory syncytial virus-infected mice (241). Similarly, resveratrol depleted mouse natural killer cells, thereby reducing the type 2 cytokines and ameliorating the airway disease (139).

Hepatitis C Virus

Resveratrol n class="Gene">multimers (oligostilbenoid compounds) were identified as potent replication inhibitors of hepatitis C virus (HCV), which contains a single-stranded positive RNA genome and has infected 170 million people worldwide (195). Among the oligostilbenoids [e.g., ampelopsin A, (+)-ε-viniferin, wilsonol C, vitisin A, and vitisin B], the resveratrol tetramer vitisin B is the most powerful to affect anti-HCV activity [EC50 = 6 nM and 50% cytotoxic concentration (CC50) > 10 μM] via neutralization of its NS3 helicase in several cell lines (154). Similarly, the more stable (+)-ε-viniferin dimer markedly lowered viral protein expression and HCV replication with minimal cytotoxicity in vitro and in vivo (127). In view of their promising antiviral and pharmacokinetic properties, oligostilbenoids warrant further anti-HCV therapeutics investigation, which will help reduce chronic liver diseases (e.g., liver cirrhosis and hepatocellular carcinoma) in HCV-positive carriers.

Epstein-Barr Virus

In preclinical studies, resveratrol disclosed preveene">ntion capacity n class="Gene">malignant transformation of human B cells in response to Epstein-Barr virus (EBV) along with potent antitumor activities against EBV-transformed B cells (66). Therefore, resveratrol is a promising avenue, unlike the classical immunosuppression approaches that lead to severe EBV reactivation with possible lymphoproliferative disorders (168). The mechanisms proposed for resveratrol include reduced miR-155 and miR-34a expression in EBV-infected B cells along with significantly declined anti-apoptotic viral gene BHRF1 expression, thereby interfering with crucial processes implicated in EBV transformation and the survival of human EBV-transformed cells (66). Recently, another mechanism was described in extranodal natural killer (NK)/T-cell lymphoma cell lines (NT-8, SNK-10, and SNT-16), resting on the curtailment of AKT and Stat3 phosphorylation, as well as activated DNA damage response and Zta upregulation of EBV, knowing that Zta induces EBV into lytic phase and viral replication (207). However, clinical trials are required to determine whether resveratrol alone or combined with available treatments could constitute a definite advantage to combat EBV-related cancers (i.e., Hodgkin’s lymphoma, Burkitt’s lymphoma, and diffuse large B-cell lymphoma, nasopharyngeal carcinoma).

Human Immunodeficiency Virus Type 1

Although resveratrol could not stop n class="Species">HIV-1 and related mutant replication in activated T cells or in transformed T-cell lines (41, 93), it does potentiate inhibition of reverse transcription by nucleoside analog reverse transcriptase inhibitors, including tenofovir, didanosine, zidovudine, and emtricitabine (47). Additional reports emphasized anti-HIV activities by demonstrating cellular ribonucleotide reductase inhibition, causing a marked decrease in 2-deoxynucleotide 5′-triphosphate (dNTP) levels, which boosts the competition of nucleoside analog drugs for cellular dNTPs in U373-MAGI cells (178). Recently, resveratrol drastically arrested HIV-1 infection through the obstruction of generation of reverse transcripts in CD4 T cells (33). This is a promising set of findings, although reinforcement is necessary to support the potential use of resveratrol as an adjuvant in anti-HIV prophylaxis formulation.

Varicella-Zoster Virus

Resveratrol adn class="Gene">ministration to human diploid MRC-5 cells resulted in the inhibition of varicella-zoster virus (VZV) replication in a dose-dependent manner (60). In fact, resveratrol affects the first stage of VZV replication by suppression of the synthesis of IE62, an essential immediate early viral protein (58).

Catechins and Various Types of Viral Infections

Catechins are n class="Chemical">polyphenolic flavonoids contained in green tea leaves (Camellia sinensis) and they include: (−)-epigallocatechin-3-gallate (EGCG), (−)-epicatechin-3-gallate, (−)-epigallocatechin, and (−)-epicatechin (57, 235). Catechins provide diverse health benefits such as antioxidants (197), anti-inflammatory (236), antitumor (18), antiobesity, antidiabetic, hypotensive, and anti-allergic effects in humans (147). Studies have shown that catechins, particularly EGCG, have antimicrobial (Gram-positive and Gram-negative bacteria) (87) and antiviral activities with different modes of action (202). The negative effects of catechins were reported, mostly in cultured cells, against a wide range of DNA viruses, including HSV (43, 172), human papillomavirus (90), and hepatitis B virus (91); against (+)-RNA viruses such as HCV (23), ZIKV (29, 220), DENV (173), West Nile viruses (220), Chikungunya virus (CHIKV; Togaviridae) (141), and porcine reproductive and respiratory virus (245); and against (−)-RNA viruses such as HIV (131), Ebola virus (180), and influenza virus (188).

The different mechaene">nisn class="Gene">ms of action triggered by catechins are largely reported in the scientific literature (113, 234). Overall, natural catechins may inhibit viral activity of enveloped DNA, (+)-RNA, and (−)-RNA viruses, but EGCG appears to be the most promising in achieving this function. Through its interactions with viral membrane proteins or/and cellular proteins, EGCG exhibits high ability to block the early stages of infections, including attachment, postadsorption entry, and genome replication by inhibiting reverse transcriptase in vitro and in vivo (113). Importantly, polyphenol 3-galloyl and 5′-OH groups possess a superior inhibitory power.

To date, maene">ny con class="Gene">mpanies and academic research groups around the world have focused on searching and developing the specific vaccine or antiviral drug to prevent or control emerging infection of SARS-CoV-2 (e.g., vaccines, monoclonal antibodies, and small-molecule drugs). However, these options need several months to years for the developing process. For the urgent requirement to alleviate the COVID-19 pandemic, the use of polyphenols and repurposed existing antiviral drugs approved for treatment of other viral infections, such as HIV, hepatitis B virus, HCV, and influenza, is somewhat promising based on previous success of the therapeutic treatment with two relevant human coronaviruses, including SARS-CoV and MERS-CoV.

POLYPHENOLS AND SARS-COV-2 CELL ENTRY

3-Chymotrypsin-Like Protease

3-Chymotrypsin-like protease (n class="Chemical">3CLpro) is a nonstructural protein of coronaviruses, which has been identified as the most attractive target to combat sarcoviruses. Its function consists in cleaving polyproteins into viral replication-related proteins, an essential process for the replication and maturation of sarcoviruses. SARS-CoV-2 also has the 3CLpro with 96.1% sequence identity compared with the SARS-CoV family, such as SARS-CoV and MERS-CoV. Another crucial function of the 3CLpro is the cleavage of host proteins related to innate immune response, among them the powerful signal transducer and activator of transcription 2 and NF-κB transcription factor as an essential modulator-signaling protein (167). Thus, neutralizing 3CLpro can serve a twofold objective regarding SARS-CoV-2 infection, e.g., averting viral maturation and restoring the natural immune response. A series of inhibitors was reported to act against 3CLpro from CoVs to prevent viral replication since the SARS outbreak in 2003 (112, 237).

As mentioned previously, the n class="Chemical">water-soluble flavonoid quercetin displays the capacity to inhibit a wide range of viruses, such as the human T-lymphotropic virus 1, the Japanese encephalitis virus, the DENV-2, and HCV (38, 108). Its main mode of action is the suppression of 3CLpro (12). Molecular docking studies and enzymatic inhibition assays clearly documented 3CLpro binding and inhibition by quercetin-3-β-galactoside (36). Based on the similarity between the 3CLpro physical structure and function, it can be plausibly deduced that quercetin may bind to the 3CLpro of SARS-CoV-2 and impede its catalytic activity similar to its effects on the various aforementioned viruses. The advantage of the quercetin small molecule is that it is abundant in nature and can easily be extracted from fruits, vegetables,grains, and leaves on a large scale, and in different formulations as well, including quercetin-3-O-β-d-glucuronide, quercetin-enriched lecithin formulations, and quercetin 7-rhamnoside, which exhibit high efficacy against different viruses (231). Among other benefits, quercetin as a natural compound has low cell toxicity activities and has been found to accumulate in various tissues, including the lungs (132), which will facilitate the interaction with SARS-CoV-2. Importantly, not only does quercetin exert inhibitory activity and replication by interactions occurring in the 3CLpro’s active site, but it might also fight concomitant comorbidities (T2D, obesity, chronic respiratory disease) characterizing old patients (95, 100). Notably, quercetin reduces pulmonary arterial pressure through the abolition of pulmonary artery smooth muscle cell proliferation and inhibits the plate-derived growth factor receptor β signaling pathways, thereby exhibiting potential cardiovascular protective effects probably by equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas (244). Finally, pulmonary SARS-CoV-2 infection may be complicated by secondary bacterial infection, and again quercetin may provide protection against clinical pneumococcal infections, even in resistant Streptococcus pneumoniae pathogenesis (143).

Transmembrane Serine Protease TMPRSS2

Virus cell entry also depends on S protein priming by host cell proteases to pron class="Gene">mote infection. TMPRSS2 (also known as epitheliasin) activity is key for SARS-CoV-2 spread and pathogenesis of infected host tissues (Fig. 3) (97). It also has the capacity to cleave ACE2 to promote viral entry (94). However, little is known about its biological function and regulation. Protease inhibitor drugs may strategically be designed to block the active site of these proteolytic enzymes, which may produce a significant reduction in SARS-CoV-2 activation in humans. For example, mimetic peptides could block the activities of TMPRSS2 and TMPRSS11D, which stimulate influenza infection by A/Memphis/14/96 (H1N1), A/Mallard/Alberta/205/98 (H2N9), and A/Texas/6/96 (H3N2) in lung epithelia (13). Although polyphenols have been the focus on the development of various antiviral proteases (e.g., SARS-CoV 3-chymotrypsin-like protease and papain-like protease, MERS-CoV cysteine proteases) against CoV-induced diseases (165), no specific study has been devoted to TMPRSS2. However, it is important to remember that polyphenols are endowed with the properties of potentially useful broad-spectrum antiviral agents based on their activity on a variety of enveloped viruses (229). Furthermore, polyphenols have α-glucosidase inhibitory activity responsible for the removal of terminal glucose residues from N-glycan chains attached to nascent glycoproteins, extremely essential for viral envelope (34). Preventing enzymatic activity by polyphenols thwarts folding and function of many glycoproteins, which are central for nucleocapsid formation (34). Concentration efforts on the polyphenol knowledge development would help design effective therapeutic and prophylactic SARS-CoV-2 inhibitors.

Angiotensin-Converting Enzyme 2

ACE2 receptors function as a gate for the n class="Species">SARS-CoV-2 (97, 224). This transmembrane protein is found on the cell surface of various tissues (e.g., nasal mucosa, lung parenchyma, gastrointestinal and renal tract, vascular endothelium, lymphoid tissues, reproductive system, and cerebral neurons) and may theoretically give the virus access to several organs (133, 242), which explains respiratory problems (pneumonia leading to acute respiratory distress syndrome) and disorders of heart, kidneys, and digestive tract. The S spike protein of SARS-CoV-2 displays a strong binding affinity for ACE2, probably due to the four-residue motif from 482 to 485 in the human ACE2 ridge (78, 224). Following endocytosis and membrane fusion, viral RNA is transcribed by the host cell ribosomes in the ER to produce viral component proteins, allowing the assembly of full viruses and discharge from the cell. Downregulation of ACE2 is known to occur following viral infection and may lead to angiotensin II effects, such as hypertension, enhanced inflammation, and thrombosis (2, 68, 204). Patients with structural variations of ACE2 receptors have an enhanced protection given the low binding affinity of the S protein (81).

The strategy of supercomputer-based in silico drug-docking to the n class="Disease">COVID-19 viral spike protein allowed the identification of quercetin as a likely ligand of ACE2, which may interfere with virus-host interactions (32).

Resveratrol has the ability to upregulate n class="Gene">ACE2 protein expression in various cardiometabolic conditions and displays protective actions against oxidative stress (OxS), inflammation, platelet oxidation, thrombus formation, and aortic aneurysm (69, 221). In the cardiovascular context, resveratrol lessened reactive oxygen species (ROS) concentration and proinflammatory cytokine production while preventing arterial aging in association with reduced activity of the PRR-ACE-Ang II axis and stimulation of the ACE2-Ang-(1–7)-ATR2-MasR axis (118). Similarly, resveratrol exerts protective effects on aging kidneys by decreasing OxS, inflammation, and fibrosis through Ang II suppression and MasR activation (109).

Because resveratrol is eene">ndowed with the ability to upregulate n class="Gene">ACE2 protein expression, we might then think that the polyphenol would promote viral infection and subsequent symptoms as ACE2 protein expression is required for SARS-CoV-2 host cell entry. Validation is obtained in ACE2 knockout mice, which become resistant to SARS-CoV-2 infections (105, 123). Despite this, ACE2 activity plays a protective role because acute lung injury and respiratory distress syndrome are more severe in mice with ACE2 inactivation following SARS-CoV-2 infection (106). Obviously, after being infected, animals with total ACE2 deficiency exhibited worsened vascular permeability, lung edema, neutrophil accumulation, and lung dysfunction. Amelioration was recorded with the administration of catalytically active recombinant ACE2 protein (15, 106, 151). Therefore, resveratrol may help mitigate the detrimental viral impact.

Dipeptidyl Peptidase 4

Dipeptidyl peptidase 4 (n class="Gene">DPP4), also known as cluster of differentiation 26 and as an antidiabetic drug, is another host receptor for COVID-19 (46). This serine exopeptidase has capacity in hydrolyzing several substrates with proline or alanine residue at position 2 and is expressed ubiquitously in several tissues such as lung, kidney, liver, gut, and immune cells, but it can also be found in a soluble form in the circulation (99). Given its ability to cleave numerous substrates, including growth factors, chemokines, neuropeptides, and vasoactive peptides, DPP4 is considered as a regulator in multiple physiological 11processes (62, 119, 160). Using a docked complex model of the SARS‐CoV‐2 spike glycoprotein and DPP4, a large interface was observed, predicting DPP4 as a functional receptor (62). Furthermore, human DPP4 has recently been noted to interact with the S1 domain of the viral spike glycoprotein (219). Even if validation is eagerly awaited concerning the question of whether DPP4 is directly involved in SARS‐CoV‐2 cell adhesion/virulence, some investigators think that DPP4 inhibition may represent a therapeutic strategy to slow the progression of COVID-19 infection or at least to modulate inflammation and fibrotic activity. To substantiate this claim, scientists mention the aptitude of DPP4 to reduce the production of proinflammatory cytokines, severity of symptoms in autoimmune encephalomyelitis myelin basic protein-specific CD4+ T-cell clones, the risk of incident autoimmune diseases, pulmonary fibrosis, and especially lung injury via lowering inflammatory cytokines in an experimental model of acute respiratory distress syndrome, which represents the main death cause of SARS-CoV-2 infected patients (193, 200). On the other hand, human DPP4 was identified as a functional receptor for the spike protein of the MERS-CoV (176) using antibodies against it (176). A preventive role against HIV1 was also evidenced with the inhibition and downregulation of DPP4 (79). Additionally, mice were made susceptible to MERS-CoV by expressing human DPP4 (124). Finally, upon inoculation with MERS-CoV, human DPP4−/− mice supported virus replication in the lungs (212).

Whether DPP4 inhibition represeene">nts a plausible approach to n class="Gene">mitigate COVID-19 requires much work to be done, as other studies reported divergent findings. The largely used inhibitors (e.g., sitagliptin, alogliptin, vildagliptin, saxagliptin, linagliptin) bind to the catalytic site of DPP4, whereas SARS-CoV-2 is directed to another DPP4 pocket site (219) and without interference with DPP4 inhibitors (65).

Experimental evideene">nce showed that n class="Chemical">polyphenols inhibit DPP4 and stimulate intestinal L cells to secrete GLP1, a DPP substrate (61). Similarly, resveratrol, cocoa-contained flavonols and polyphenol-rich grape seed-contained catechin, epicatechin, procyanidin B2, and gallic acid were able to inhibit DPP4 activity (61, 208). The administration of the resveratrol phytochemical in presence of DPP4 inhibitors (alogliptin, sitagliptin, saxagliptin) slowed down the metabolism rate of these drugs while extending their pharmacological effects (208). Given its potential, resveratrol may achieve synergistic actions with pharmacological agents particularly in diabetic patients who contract COVID-19 and have worse prognosis (83, 225). Of note, diabetic ketoacidosis, hyperosmolar hyperglycemia state, and acute metabolic complications are precipitated by COVID-19 infection, resulting in catastrophic outcomes (21). Because COVID-19 has diverse disproportionately worse outcome, especially in patients with preexisting T2D, hypertension, and cardiovascular disease, administration of polyphenols known to alleviate these disorders can be a major source of benefit. For example, persons that consume polyphenol-rich foods can reduce the risk of T2D (189). This section will be developed below.

POLYPHENOLS AND VIRAL SIRTUIN REGULATION

SIRTs (1–7) represent a large family of n class="Chemical">NAD+-deacetylase enzymes with a broad range of physiological and biological functions, such as the regulation of gene expression, cell survival, apoptosis, energy metabolism, circadian clocks, mitochondrial biogenesis inflammation, DNA repair, development, neuroprotection, and longevity (86). For example, the most studied SIRT1 splits the nicotinamide ribosyl bond of NAD+ and transfers the acetyl group from proteins to their cosubstrate through an ADP-ribose-peptidyl imidate intermediate. Recently, mounting attention has been paid to the anti- and proviral role of SIRTs in viral infection control, as acetylation constitutes a significant regulatory process in infection.

Oligonol, a n class="Chemical">polyphenolic antioxidant compound, shows anti-influenza activity (75). Its administration in human lung epithelial cells, after influenza virus infection, simultaneously upregulated SIRT1 expression and downregulated viral hemagglutinin expression (166). Accordingly, SIRT knockout or addition of SIRT antagonists in human MRC-5 embryonic lung fibroblasts or canine MDCK kidney epithelial cells stimulated the growth of diverse human viruses (human pathogen human cytomegalovirus, influenza A H1N1 virus) (122).

Similarly, n class="Gene">SIRT1 overexpression resulted in HIV transcription, whereas SIRT1 lessening by siRNAs or inactivation by nicotinamide increased viral gene expression via multifunctional Tat protein‐induced HIV‐1 transactivation (243). An opposing outcome (probably due to differences in their experimental conditions) was reported by another study, which documented that SIRT1 directly binds to Tat to deacetylate it and synergistically activate the HIV promoter transcription (161).

Stimulation of n class="Gene">SIRT1 by resveratrol repressed human T-cell leukemia virus type 1 (HTLV-1) replication (210). Mechanistically, activation of SIRT1 by resveratrol was seen to inhibit HTLV-1 transcription by blunting and counteracting the activity of Tax oncoprotein, the viral transcriptional regulator. This is the first proof of concept for the effectiveness of resveratrol as a SIRT1 modulator and as an antiviral defense molecule for poorly treatable HTLV-1, causing aggressive adult T-cell leukemia in ∼20 million people worldwide.

As well documented above, n class="Chemical">polyphenols display antiviral effects against a variety of viruses via different cellular pathways by actuating SIRT1, a central actor-providing defense against viral pathogens. Like a certain number of virus types, SARS‐CoV‐2 may act to deviate sirtuins from their regular physiological processes. Unfortunately, the surprising outbreak of COVID-19 did not leave scientists with enough time to scrutinize its molecular mechanisms by which disease-causing SARS‐CoV‐2 dramatically infects and replicates in human cells and concomitantly probe the status of SIRTs and histone/nonhistone targets. As SIRT1 holds promise to have a broad impact in the field of infectious diseases, it is possible that its activation by polyphenols may exert protective effects against SARS‐CoV‐2. It has already been established that resveratrol is able to activate SIRT1, which is able to modulate ANG type 1a receptor and ACE2 (146). It is therefore mandatory to assess whether the modulation of SIRT1 expression by polyphenols in COVID-19 presents a new insight in the discovery of a number of therapeutics.

POLYPHENOLS AND MODIFICATION OF RESPIRATORY AND INTESTINAL MICROBIOTA

Viral infections disturb synergistic aene">nd con class="Gene">mpetitive/antagonistic interactions of microbial communities in respiratory and intestinal systems. The resulting dysbiosis, which reflects abnormal microbiota diversity and composition, affects local and general health. If the microbiota-host interplay in normal conditions promotes immune homeostasis (26, 156), viral infection in turn instigates microbiota alterations along with immune pathogenesis while upsurging infectious diseases and leading to the disruption of physical barriers, dysregulation of immune responses, and delays in a return to homeostasis (26, 209).

Upper Respiratory Tract

Comn class="Species">mensal and pathogenic bacteria, including Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrahlis, Staphylococcus aureus, and Neisseria meningitidis constitute the microbiota in the nasopharynx of healthy humans (92, 203). However, viral infections of the upper respiratory tract modify bacterial adherence (10), phyla, and diversity (126), as well as host immune response (149). There is a common understanding that viral infection leads to microbiota shift and dysfunction in the upper respiratory tract, in association with secondary bacterial infections and disease, as exemplified by infective human rhinovirus and respiratory syncytial virus (103). Clusters of H. influenzae and Streptococcus were positively linked to respiratory syncytial virus infection and hospitalization (187), but commensal Corynebacterium pseudodiphtheriticum alleviates respiratory syncytial virus and S. pneumoniae superinfection (114).

Lower Respiratory Tract

If viral infections are usually traene">nsitory aene">nd restricted to the upper n class="Species">respiratory tract, their severity can make them progress to the lower respiratory tract along with marked morbidity and mortality. In this context, alterations of microbiota have been described in the lower respiratory tract after influenza viral infection (82). During the acute period, this site microbiota was characterized by an abundance of the genera Halomonas, Shewanella, and Clostridiales, whereas Bacillales and Actinobacteria were the preponderant genera in the recovery period. Furthermore, the enrichment with Gammaproteobacteria and pulmonary gram-negative pathogens like Acinetobacter, Pseudomonas, and Stenotrophomonas and facultative anaerobes such as Staphylococcus Streptococcus and the anaerobe Prevotella in Bacteroidetes can cause pneumonia. Similarly, the lower airway microbiota of Ugandan HIV-infected acute pneumonia patients contained dominant bacterial family (Prevotellaceae, Streptococcaceae, or Pseudomonadaceae) (194). Furthermore, dysbiosis and dominance of Enterobacteriaceae were noted in influenza A virus-infected lower respiratory tract (179).

Gastrointestinal Tract and Gut–Lung Axis

Although the shift and function of gut n class="Gene">microbiota in response to viral pathogens remains poorly studied, the literature available for the moment indicates marked changes in gut microbiota composition in association with immune activation and chronic inflammation, as is the case for HIV (9), hepatitis B virus (228), HCV (107), and rotavirus (73). Consequently, the viral replication is accompanied by defects in epithelial barrier integrity and immune homeostasis, leading to microbial translocation that, in turn, contributes to immune activation, inflammation, and disease progression. Therefore, changes of gut microbiota communities and functions in response to viral infection may lead to adverse clinical outcomes.

Similarly, n class="Disease">dysbiosis and subsequent dysregulation of gut microbiota-related immunological processes are observed in respiratory diseases following respiratory infection by viruses such as influenza A virus (239), respiratory syncytial virus (226), and recombinant pneumonia virus (64) exhibiting tropism for the gastrointestinal tract and additional systems. Importantly, accumulating data underline the mutual interactions between intestinal microbiota and the lung with effects of respiratory infections (Fig. 4) (148). Disturbances of gut microbiota raise the risk of respiratory syncytial virus infections in infants (22). Otherwise, the gut microbiota in physiological conditions mediates the differentiation and expansion of regulatory T cells (Treg) (211), whereas mononuclear phagocytes’ intestinal and respiratory tract sample antigens in the lumen possibly act through metabolites (e.g., short-chain fatty acids), thereby fine-tuning the threshold of antiviral immune responses and activating adaptive immunity to promote the clearance of viruses and other pathogens (22). Although the gut–lung interactions, notably gut microbiota-lung immunity (referred to as the “gut–lung axis”) (Fig. 4) appear more and more important for respiratory diseases (63), the cross-talk between their respective microbial communities is ill defined, particularly during viral infections. Factors disturbing gut microbiota (e.g., smoking, antibiotics, diets, pre- and probiotics) cause inflammation and predispose to microbial infection at distal organs such as the lung (22). Just to name a few examples: fecal transplantation induces changes in the lung microbiota (145); intestinal germ-free animals are protected from lung injury (205); and the modification of gut microbiome is closely implicated in the pathogenesis of the acute respiratory distress syndrome (54). Reciprocally, lung microbiota may bear upon gut microbiota composition as reflected by influenza infection, which enhanced Enterobacteriaceae and lowered Lactobacilli and Lactococci in the intestine (140).

Impact of Polyphenols on the Gut-Lung Axis in the Context of Viral Infection

Although the respiratory tract is aln class="Gene">most exclusively invaded by human influenza viruses, infected individuals very often suffer from gastrointestinal symptoms (55). Investigations, designed to elucidate the mechanisms, found that this infection unbalanced gut microbiota through the induction of type I INFs (52). Conversely, probiotics and prebiotics, which reinforce gut microbiota (14, 27, 31, 50, 96, 183, 191, 217), ameliorate the immune system and influenza virus-related damage (25, 177, 218, 230), suggesting that gut microbiota manipulation represents a tool to treat lung infections and related diseases.

In addition to the hydrolysis of dietary fibers and polysaccharides by intestinal n class="Gene">microbiota, leading to the production of short-chain fatty acid metabolites with anti-inflammatory and immunomodulatory capabilities, polyphenols emerge as powerful prebiotics (116). They can be catabolized, deglycosylated, and biotransformed in strong metabolites by gut microbiota, with evident health host benefits (28). By exerting specific effects on bacterial strains (e.g., reducing pathogens and enhancing favorable communities), polyphenols can sustain gut–lung axis integrity and provide protection against viral infections (Fig. 4). As its name suggests, SARS-CoV-2 is linked to an acute respiratory syndrome, but also to gastrointestinal (GI) symptoms (diarrhea, vomiting, nausea, abdominal pain) (247). The GI manifestations not only coexist but may also precede the respiratory events (98, 170). As normal gut microbiota restoration may influence the immune response to viral diseases and improve respiratory symptoms, polyphenols known as powerful prebiotics may represent an efficient therapeutic arsenal to fight the fatal COVID-19. This is all the more important because the gut microbiome of COVID-19 patients has been reported to be affected and may predict the severity of the disease.

POLYPHENOLS AND VIRAL INFLAMMATION

Following viral infection, it is possible to observe dysregulated host in class="Gene">mmune response and production of inflammatory cytokines. COVID-19 patients exhibit elevated concentrations of plasma IL2, IL6, IL7, IL10, granulocyte colony-stimulating factor (GCSF), IFN-γ-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1-α (MIP1A), and TNFα (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 agents capable of boosting antiviral response.

Fig. 5.

Possible mechanisms of polyphenols against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The multiple biological properties may be actuated to counteract viral infection and related complications. 3CLpro, 3-chymotrypsin-like protease; ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl peptidase 4; TMPRSS2, transmembrane protease serine 2.

Possible mechaene">nisn class="Gene">ms of polyphenols against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The multiple biological properties may be actuated to counteract viral infection and related complications. 3CLpro, 3-chymotrypsin-like protease; ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl peptidase 4; TMPRSS2, transmembrane protease serine 2.

POLYPHENOLS AND VIRAL OXIDATIVE STRESS

A molecular link is appareene">nt betweeene">n n class="Disease">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 S-transferase 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.

POLYPHENOLS AND CARDIOMETABOLIC DISORDERS

Preexisting cardiometabolic ailn class="Species">ments display poorer prognosis for the COVID-19 course. Available epidemiological information from the United States indicates that at least 25% of patients who perished following COVID-19 had obesity (233). Elevated body mass index was predictive of the need for hospitalization (169) and related to admission to the intensive care unit (134). The mechanistic link is probably the induction of inflammation by the immune system in the adipose tissue, increasing the vulnerability to develop infections (115). Notably, adipose tissue is composed of adipocytes, macrophages, endothelial cells, and lymphocytes (30), which secrete, among others, adipokines, cytokines, and chemokines with a substantial influence on surrounding tissues, allowing a potential cross-talk with the respiratory system (40). Not only may the adipose tissue serve as a pathogen reservoir for SARS-CoV-2 given its high ACE2 expression (146), but its obesity-associated inflammation likely plays a role in cardiometabolic pathogenesis and, of course, in the aggravation of viral outcomes.

In a compreheene">nsive n class="Gene">meta-analysis totaling 4,659 patients, additional metabolic complications (e.g., T2D, hypertension, coronary heart disease) have been noted to be closely associated with an enhanced COVID-19 death risk (213) and adverse outcomes (67). In these conditions, investigators propose that compounding SARS-CoV-2 infection and T2D provokes dysregulated immune response, which leads to aberrant immune response with exacerbated and extended lung pathology (124).

Consequently, use of polyphenols in controlling the n class="Disease">cardiometabolic disorders (Fig. 6) appears as a biocontrol strategy to reduce the chances of viral infection and/or exaggerated adverse outcomes of SARS-CoV-2. These bioactive molecules yield beneficial effects via regulation of multiple metabolic pathways, which promote antioxidants and anti-inflammatory, antithrombotic, anti-atherogenic, and antiviral effects (Fig. 5) (147). What is more, growing evidence reveals that polyphenols reduce body weight, modify body composition, and subvert systemic and adipose tissue inflammation while ameliorating metabolic diseases (129). The constellation of risk factors of the metabolic syndrome, including dyslipidemia, insulin resistance, hypertension, and obesity, responds advantageously to polyphenols (Fig. 6) (24). Consistent antidiabetic and cardioprotective effects are observed following administration of polyphenolic flavonoid experimental models and human studies (11, 111, 214). Therefore, polyphenols may represent a promise to mitigate SARS-CoV-2-associated metabolic disorders and atherosclerosis risks, especially diabetes mellitus and cardiovascular diseases as principal comorbidities. However, it should be pointed out that despite their health-promoting effects, polyphenols have limited bioavailability, as a substantial proportion is lost during the digestive process and only a small fraction is directly absorbed by the small intestine. In fact, the bulk of polyphenols reaches the colon, where they interact with the gut microbiota and regulate microbial growth/proliferation. For their part, intracolonic microorganisms are crucial for polyphenol metabolism to produce bioactive metabolites that exert evident health benefits.

Fig. 6.

Beneficial effects of polyphenols against diverse disorders mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This illustration summarizes the main health benefits of polyphenols in pathological conditions, which can be built upon and produce beneficial results in the threatening coronavirus disease (COVID-19).

Beneficial effects of polyphenols against diverse disorders n class="Gene">mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This illustration summarizes the main health benefits of polyphenols in pathological conditions, which can be built upon and produce beneficial results in the threatening coronavirus disease (COVID-19).

The potential mechaene">nisn class="Gene">ms 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.

Given the lack of vaccine and effective antiviral agents for COVID-19, evideene">nce is provided to propose that natural n class="Chemical">polyphenolic compounds may serve as a useful arsenal to mitigate coronaviral infection in view of their established beneficial properties and functions.

The effectiveness of polyphenols has beeene">n first substaene">ntiated by their powerful aene">ntiviral activities, as reflected by the n class="Gene">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 SARS-CoV-2) and transmembrane proteases (e.g., TMPRSS2 mediating SARS-CoV-2 cell invasion).

As amply supported by the scieene">ntific literature, n class="Chemical">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 n class="Chemical">polyphenols, which may both amend dysbiosis triggered by invading SARS-CoV-2 and boost antiviral response, thereby turning down viral infectivity.

Bioactive polyphenols are known to in class="Gene">mprove 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 paene">nden class="Gene">mic 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, anti-inflammatory, 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.

The direct impact of n class="Chemical">polyphenols on SARS-CoV-2 infectivity and mechanisms of action deserves an in-depth investigation.

Emerging aene">nin class="Gene">mal models for coronavirus should be exploited to progress and gain insights into the protective role of polyphenols against SARS-CoV-2 entry and reproduction in host cells.

Intensive efforts are highly needed to carry out clinical trials to test the effectiveness of polyphenols in suppressing n class="Species">SARS-CoV-2 replication and inflammation while reversing organ failure.

Polyphenols will have to be con class="Gene">mprehensively evaluated on preexisting inflammatory and cardiometabolic conditions to get COVID-19 prognosis and outcomes.

Information is required as to the safety, stability, aene">nd bioavailability of n class="Chemical">polyphenols along with the interactions with antiviral drugs.

GRANTS

This study was supported by the Canadian Institutes of Health Research Grants (PJT 153113), NSERC (RGPIN-2016-04761), Leahy Orchards Inc., and the J. A. DeSève Research Chair in Nutrition.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

E.L. and S.S. prepared figures; E.L. and S.S. drafted maene">nuscript; E.L., E.D., V.n class="Gene">M., and S.S. edited and revised manuscript; E.L., E.D., V.M., and S.S. approved final version of the manuscript.