The use of natural and alternative therapies for the prevention and treatment of viral infections focuses on key nutrients that inhibit viral entry, reduce viral replication and balance the inflammatory reaction to infection. While  avoiding exposure to SARS-CoV-2 is ideal, some may not be so lucky. Those who work with the public are at increased risk of contracting the virus; therefore, taking some reasonable precautions to decrease the chance of infection and reduce the severity if they do get the virus may be prudent. In this 3-part blog series, I will discuss 3 important nutrients that have the ability to enhance our immune function against viral infection as well as regulate the inflammatory response to the virus: quercetin, zinc and vitamin C. In this first part I will discuss quercetin.

When and how to intervene with naturopathic therapies

There are 2 distinct phases of the COVID-19 disease during which we can appropriately intervene to reduce the severity and duration of illness. The first phase of intervention involves reducing viral replication, resulting in decreased viral load. The second phase of intervention involves control of the inflammatory response to the infection itself. How we intervene in these distinct phases is crucial to outcomes. The first phase requires enhancing the immune response to inhibit viral replication while the second phase requires management of the immune response to prevent it from spiraling into a state of uncontrolled inflammation or a cytokine storm. Consideration of comorbidities such as older age, gender, diabetes, and cardiovascular disease are important determinants of care as those with predisposing conditions may enter the second phase of illness more rapidly and severely than those without comorbidities.

The ability of our immune system to respond favorably to viral infections requires a healthy reserve of each of these nutrients prior to viral exposure. Daily consumption of specific nutrients and natural compounds through diet and supplementation provides the greatest benefit for prevention and treatment of viral infections. Quercetin has a strong safety profile with supplementation of up to 1 gram per day for several months without significant adverse effects.

What is quercetin?

Quercetin is a flavonol, one of the 6 sub-classes of flavonoids within the category of polyphenolic compounds. Quercetin is most commonly known for its anti-inflammatory and antioxidant properties and is frequently found in herbal and nutritional formulas used to treat allergies and inflammation. Additional attributes of quercetin include its ability to function as an antiviral compound as well as inhibit lipid peroxidation, platelet aggregation and capillary permeability. It has also been noted that quercetin stimulates mitochondrial biogenesis, has immunoprotective properties, and is anticarcinogenic [1]. Quercetin has become a supplement of choice in the battle against respiratory viral infections because of its specific regulatory activity on the inflammatory processes that are triggered by the immune response. A recent article in Frontiers in Immunology suggests that quercetin supplementation may provide immunoprotective, anti-inflammatory, antioxidant, and antiviral activity [2]. The targeted antiviral action of quercetin is potentiated and regenerated by the simultaneous ingestion of vitamin C [2]. It has also been noted that quercetin potentially acts as a zinc ionophore which can increase the intracellular zinc concentration contributing to zinc’s ability to inhibit viral replication.

Antiviral properties of quercetin

Most of the studies on quercetin analyzing its antiviral capacity are done in vitro and are carried out in the presence of a variety of viruses, including several members of the Coronaviridae family. As noted by Li and coworkers, quercetin demonstrates anti-pathogenic capacity when cultured with target cells in the presence of rhinoviruses, adenoviruses and coronaviruses [1]. Animal studies have shown quercetin’s promise as an effective antiviral, particularly in the lungs, if quercetin has been administered prior to infection [2]. A recent study found that “a flavonoid derivative called quercetin 3-β-O-d-glucoside (Q3G) has the ability to protect mice from Ebola even when given as little as 30 min prior to infection” [3]. It was noted that quercetin interfered with the early steps of viral entry and was effective as an antiviral against 2 distinct species of Ebola virus. Like Coronaviruses, Ebola is an RNA virus and many of the medications that have been used in the treatment of Ebola have been considered for SARS-CoV-2.

Human studies on quercetin for viral infections

The literature reports only 3 human clinical trials on the use of quercetin and the prevention and treatment of viral infections. All 3 studies were double-blind, placebo-controlled randomized clinical trials and were conducted in outpatient settings through the World Health Organization. Two of the studies involved participants who were trained athletes, while the third included a diverse range of 1023 healthy and unhealthy individuals from the community to determine the effects of quercetin in preventing illness. The 2 trials involving athletes assessed the onset of respiratory illness after competitive athletic events resulting from stress-related immunosuppression. Quercetin supplementation resulted in a successful reduction in the illness rates of exercise-stressed athletes as well as a positive augmentation of their innate immune function. Based on these human clinical trials, a review in Advanced Integrative Medicine determined that oral quercetin may have a beneficial effect on the incidence and duration of respiratory tract infections in certain populations [4].

Mechanisms of antiviral actions

In the presence of viral infections, quercetin exerts its effects by inhibiting polymerases and proteases and binds viral capsid proteins, thus preventing viral replication and entry. Polymerases and proteases are central to virus genome replication and transcription and are often targets for drug development. Viral capsid proteins function to protect viral RNA or DNA and allow the virion to attach to a host cell, which provides proteins that enable the virion to penetrate the host cell membrane [5]. Quercetin and other flavonoids found abundantly in many foods have the collective effect of preventing viral entry into cells and show promise as broad-spectrum antivirals if cell levels are maintained prior to viral exposure.

Quercetin has the ability to block viral assembly by modulating heat-shock proteins (HSPs), which ultimately interferes with the process of viral replication. There are several HSPs, each with a numerical designation indicating the molecular weight and potential function. HSPs oversee the proper configuration of protein structures and this mechanism may be hijacked by viruses and used for viral protein replication. The marked inhibition of virus production by quercetin may be related to a reduction in specific HSPs (HSP40, HSP70) and their involvement in viral translation. In a 2009 tissue culture study, the administration of quercetin to cells infected with hepatitis C resulted in a marked reduction of viral load as a result of HSP synthesis inhibition [6]. This study concluded that HSP synthesis inhibition may be an attractive therapeutic avenue in reducing viral replication, especially in people who have HCV genotype 1 which does not respond well to the standard hepatitis C antiviral treatment protocol of interferon-gamma and ribavirin. The administration of quercetin to infected cells was successful at reducing viral load and was therefore determined to be a potentially effective adjunct in the treatment of hepatitis C with low associated toxicity.

Quercetin also fortifies the immune response by promoting early interferon production, modulating interleukins and promoting T cell maturation and phagocytic activity. Most in vitro research suggests that quercetin possesses anti-inflammatory properties and immunological improvement through its ability to modulate cell-signaling pathways that activate and inhibit various targets within the innate and adaptive immune system. Quercetin exerts benefits on cardiovascular protection, reduces hypertension and improves type 2 diabetes through various mechanisms leading to potential improvement in comorbid states associated with a poor prognosis for COVID-19 [7,8,9].

Sources of quercetin in the diet

Quercetin is found in many plant-based foods including fruits, vegetables, tea, coffee, nuts, seeds and grains. Foods with the highest concentration of quercetin are apples, citrus fruits, capers, onions, shallots, grapes, tomatoes, berries and brassica vegetables. Beverages that have a high concentration of quercetin include red wine and green tea which are also of noted benefit for their respective concentrations of resveratrol and epigallocatechin gallate (EGCG) which are 2 additional flavonoids recommended for immune and antioxidant support. The higher our consumption of color-rich, plant-based foods, the better chance we have of getting a variety of flavonoids, including quercetin. The Mediterranean diet is often discussed because of various health benefits due to its high concentration of vegetables rich in flavonoids and nutrients that work in a synergistic fashion to optimize individual health.

Pure quercetin exists in the form of an aglycone which lacks the attached sugar molecule. The aglycone version of quercetin is highly water insoluble and lipophilic. Quercetin glycoside has a sugar side chain which makes it more water soluble and increases its absorption. Differences in quercetin-conjugated glycosides affect its bioavailability. Quercetin glucoside, or isoquercetin, tends to have the best absorption as it is more bioavailable due to the highly efficient hydrolysis and absorption of glucoside chains within the enterocytes of the intestinal wall. Overall, quercetin can have variable bioavailability which is why adequate consumption of dietary sources and adequate supplementation early as a preventive measure provides the opportunity for quercetin to accumulate in cells and more readily exert its effects upon exposure to a virus. The majority of studies demonstrate that pretreatment rather than posttreatment of cells produces the best protection against viral replication and cell death.

Due to its lipophilic nature, the absorption of quercetin from foods and supplements is facilitated when consumed with dietary fats [10]. More recent formulations of quercetin involve the use of a lecithin base to create a quercetin phytosome. This formulation increases absorption of quercetin by 20 times compared to that of a standard dose of quercetin that is not encased in a phospholipid. “Quercetin Phytosome allows the oral administration of quercetin in a safe and bioavailable manner, thus facilitating the effective utilization of this natural compound to treat various human diseases” [11]. Dosage of quercetin ranges between 250-500 mg for prevention and 500-1000 mg for treatment of viral infections.

There are currently a few studies listed in ClinicalTrials.gov on the use of quercetin, either alone or in combination with other nutrients for the prevention and treatment of SARS-CoV-2 in high risk populations with dosing ranging from 500 mg to 1000 mg per day.  

Quercetin, zinc, and vitamin C supplements are inexpensive, well-tolerated and recommended for general immune support and reduction of viral illness. These nutrients also work together in a synergistic capacity to enhance their individual actions. All have a good safety profile if used at recommended dosages and can be used for long periods of time without any negative effects. Viral replication occurs early in the disease process of COVID-19 and may determine the severity of the inflammatory phase which occurs later in the disease process and has the potential to advance to a cytokine storm, especially in those with comorbid conditions and nutrient deficiencies. Early interventions to reduce viral penetration and replication and control the inflammatory response may be key to better outcomes with COVID-19. Using these nutrients preventatively as well as incorporating food sources provides the best results as it allows time for quercetin to equilibrate to optimal tissue levels. If we are adequately fortified with quercetin and other nutritional antivirals prior to viral exposure, the immune system will be better prepared to respond swiftly and effectively to help reduce the duration and severity of the viral infection and inflammatory response (cytokine storm).

In Part 2 of this 3-part series we will examine the role for zinc in supporting the immune response.

References

1. Li Y, et al. Quercetin, Inflammation and Immunity. Nutrients. 2016;8:167. 
2. Colunga Biancatelli RML, et al. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol. 2020;11:1451.
3. Qiu X, et al. Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection. Antimicrob Agents Chemother. 2016;60:5182-8.
4. Aucoin M, et al. The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review. Adv Integr Med. 2020;7:247-251.
5. Gelderblom, Hans R. Structure and Classification of Viruses. Medical Microbiology, edited by Samuel Baron, 4th ed., University of Texas Medical Branch at Galveston, 1996.
6. Gonzalez O, et al. The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology. 2009;50:1756-64.
7. Chen S, et al. Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. Mediators Inflamm. 2016;2016:9340637.
8. Serban MC, et al; Lipid and Blood Pressure Meta‐analysis Collaboration (LBPMC) Group. Effects of Quercetin on Blood Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2016;5(7):e002713.
9. Ferenczyova K, et al. Potential Implications of Quercetin and its Derivatives in Cardioprotection. Int J Mol Sci. 2020;21:1585.
10. Kaşıkcı MB, and Bağdatlıoğlu N. Bioavailability of Quercetin. Curr Res Nutr Food Sci. 2016;4(Special Issue Conference October 2016):146–51.
11. Riva A, et al. Improved Oral Absorption of Quercetin from Quercetin Phytosome®, a New Delivery System Based on Food Grade Lecithin. Eur J Drug Metab Pharmacokinet. 2019;44:169-177.