Quercetin Boosts Interferon Response to Viruses and COVID-19

Quercetin Boosts Interferon Response to Viruses and COVID-19

STORY AT-A-GLANCE

  • COVID-19 interferes with a cell’s ability to protect itself; researchers find quercetin protects cellular response and boosts type 1 interferon
  • Type 1 interferon works by signaling infected cells to produce proteins to stop the virus from replicating in the cell
  • Quercetin is also a zinc ionophore, which helps more zinc function inside cells to lower the viral load and reduce the severity of viral infections
  • Recent data show hydroxychloroquine is not as effective as hoped, yet none of the studies involved the use of zinc. This is important as hydroxychloroquine is also a zinc ionophore
  • The side effects of hydroxychloroquine caused the FDA to warn against use outside the hospital. Quercetin and zinc present an alternative without dangerous side effects when used appropriately

As the number of people who have died from COVID-19 rises, more widespread testing reveals the infection may have moved farther and faster than was anticipated. The Centers for Disease Control and Prevention recently released five planning scenarios1 “designed to help inform decisions by modelers and public health officials who utilize mathematical modeling.”

Each of the scenarios is based on numerical values and epidemiological characteristics of the viral infection, reflective of data gathered before April 29, 2020. The CDC is clear these are estimates and not predictions:2

  • There was no known pre-existing immunity before 2019 so all people in the U.S. were assumed to be susceptible
  • Between 20% and 50% of all people believed to be infected were asymptomatic; they were deemed likely to be infectious
  • The “best estimate” is 0.4% of people who show symptoms will die; for people over 65 it’s 1.3% and for those 49 and under it’s 0.05%

Although there was nearly immediate pushback,3 estimates from The Centre for Evidence-Based Medicine at the University of Oxford were similar.4 There were two numbers used to define the percentage of deaths. The case fatality rate was chosen to represent the number of deaths divided by the number of confirmed cases; it was limited by the number of people tested.

Based on the possibility that up to 50% of those infected were asymptomatic, this created an abnormally high percentage. The infection fatality rate was used to represent the number of deaths divided by the number of people infected with SARS-CoV-2. That number was far lower since it included all people who are infected and not just those whose status was confirmed with a test.

The Centre acknowledges that estimating fatality rates in the early stages of infection is subject to uncertainty. However, it’s important to note that the infection fatality rate in the 3,711 passengers on the Diamond Princess cruise ship — the ship quarantined in Yokohama for 27 days at the start of the pandemic5 — was 1.3%.6

Quercetin Boosts Cellular Response to Viruses

Even one death is too many. As I’ve written in the past, quercetin is a natural antihistamine and anti-inflammatory that lowers your risk for viral illnesses. In a recent paper, researchers identified one mechanism through which quercetin may work to control viral replication and promote health.7

Casein kinase II (CK2) is an enzyme with a diverse set of functions in the body. It is fundamental to controlling homeostasis at the cellular level. Yet, much of its functioning and mechanisms of action are still unknown.8 The enzyme is also involved in the survival and metastatic spread of cancer cells.

There is evidence that it down-regulates the ability a cell has to generate type 1 interferon when attacked by a virus. It does this by inhibiting retinoic acid-inducible gene I (RIG-I),9 which has protein sensors that signal genetic expression of type 1 interferon by identifying the replication of RNA viruses, such as SARS-CoV-2.

Researchers found that quercetin could inhibit the expression of CK2, which slowed the replication of RNA viruses in the lab and in mice.10 They pointed out that the effectiveness of supplemental quercetin may be hindered by the low solubility of the compound, which affects absorption.

By using “enzymatically modified isoquercitrin (EMIQ)” they discovered they could develop plasma levels 20 times higher than the same intake of unmodified quercetin. The authors concluded quercetin or EMIQ “should be included” in aiding the control of viral infections.

In research on the Ebola virus (EBOV) that triggered epidemics between 2013 and 2016, scientists found that the virus also suppressed type 1 interferon. They discovered that quercetin could suppress the effect on type 1 interferon and that it restored the body’s ability to protect itself:11

“Overall, quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.”

What Are Interferons?

Interferons (IFNs) are a subset of cytokines discovered in 1957.12 These cells are often the initial defense against viruses. There are two types and three forms of interferon. Within type 1 interferon, there are alpha and beta. Type II interferon has the gamma form.13

The different types are based on the function of the cytokine. Type I interferons help cells resist viruses. Type II aids in responding to infections and cancer growth. Initially, researchers hoped it could be used to treat diseases, including cancer. But it had serious side effects.

After further development, several forms were released to treat genital warts, multiple sclerosis and hepatitis B and C with varying results. The name “interferon” came from the ability of Type 1 to interfere with the virus’s ability to duplicate. A cell secretes interferons when a foreign substance, like a virus, is detected.

However, the interferon does not function by attacking the virus. Instead, it tells the infected cell and the cells that surround the infected cell to make proteins that stop viral replication. Quercetin functions to stop CK2 from interfering with the action of type 1 interferon so cells are signaled to stop viral replication.

Quercetin Works With Zinc to Stem Viral Replication

Quercetin also functions as a zinc ionophore. This is a substance that helps transport zinc through the cellular plasma membrane14 and raises the level of zinc inside the cells. It’s another mechanism through which quercetin may help lower the viral load and reduce the severity of viral infections.

Zinc has proven antiviral properties and can reduce the length of the average cold by 33%.15 Recently, scientists pointed out there were indications that maintaining normal zinc levels may help reduce the severity of COVID-19.16

In the lab, zinc has demonstrated the ability to inhibit replication of the SARS-CoV-2 virus, which researchers believe is the underlying therapeutic effect in the use of hydroxychloroquine.

Zinc may also up-regulate interferon production and the antiviral activity of the protein. Experts think it may reduce the risk of a secondary bacterial infection, especially against Streptococcus pneumoniae. Interestingly, zinc deficiency is common in older adults and in those who are obese, have diabetes or atherosclerosis.

Likely not by coincidence, these are some of the same populations who have a higher risk of severe disease from SARS-CoV-2.17 The research team who looked at past studies on zinc suggest that it has a protective effect against COVID-19 by lowering inflammation, helping clear mucus, preventing ventilator-induced damage and supporting immunity.18

In addition to the impact quercetin has on the immune system, researchers have also found it helps to ameliorate obesity, Type 2 diabetes, circulatory dysfunction, chronic inflammation and seasonal allergies.19 It has also been found to help lower blood pressure in patients with Stage 1 high blood pressure.20

Researchers have found that quercetin can trigger tumor regression and it can activate the mitochondrial pathway of apoptosis.21 This is programmed cell death, without which cells can grow uninterrupted and develop into cancerous growths.

Hydroxychloroquine: Poor Outcome With Added Risk

Two recent trials with the antimalarial drug hydroxychloroquine have yielded disappointing results. The first 75 patients at 16 Chinese treatment centers who were positive for COVID-19 were given hydroxychloroquine.22

The researchers found the primary endpoint of a reduction in the viral load, and secondary endpoints of improvement and reduction in clinical symptoms, were not significantly better than in the control group.

The group receiving hydroxychloroquine had a negative conversion of 85.4% compared to the control group of 81.3%. In addition, the group receiving hydroxychloroquine had a greater number of adverse events compared to the control group. The most common was diarrhea. The authors concluded:23

“The administration of HCQ did not result in a higher negative conversion rate but more alleviation of clinical symptoms than SOC [standard of care] alone in patients hospitalized with COVID-19 without receiving antiviral treatment, possibly through anti-inflammatory effects. Adverse events were significantly increased in HCQ recipients but no apparently increase of serious adverse events.”

In a second study published in the Lancet,24 researchers used a multinational registry of patients who were given hydroxychloroquine or chloroquine, with or without a macrolide antibiotic for treatment. This class of antibiotic includes azithromycin, which has been used in other study groups.

There were 671 hospitals over six continents that supplied data of patients who were hospitalized between December 20, 2019, and April 14, 2020. During the study period there were 96,032 patients who met the criteria; 14,888 were in the treatment group and 81,144 were in the control group.

After controlling for confounding factors, the mortality rates were compared, and the researchers were unable to find a benefit from the antimalarial drugs when they were used alone or with a macrolide. What they did find was that using the:25

“… drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.”

A third observational study, published in The New England Journal of Medicine, found using hydroxychloroquine did not improve patient outcomes with COVID-19.26 In addition the FDA has cautioned against the use of hydroxychloroquine or chloroquine as an outpatient related to the dangerous heart arrhythmia side effects from the drugs.27

What is important to note in each of these studies is the absence of zinc in the intervention groups. We now know that chloroquine and hydroxychloroquine are zinc ionophores,28 which means the main ingredient required to prevent the viral infection may not have been given.

While it is difficult to make an assumption of the efficacy of treatment of COVID-19 with hydroxychloroquine, since zinc was not given in each of these studies, it is also important to consider the secondary side effects associated with the drug, namely ventricular arrhythmias.

Dose Recommendations for Zinc and Quercetin

During the COVID-19 pandemic and future infectious disease seasons, supplementing with quercetin and zinc may be a good idea for many. It can help boost your immune system’s innate ability to ward off infectious illness. As for dosage, here are some basic recommendations:

•Quercetin — According to research from Appalachian State University in North Carolina, taking 500 mg to 1,000 mg of quercetin per day for 12 weeks results in “large but highly variable increases in plasma quercetin … unrelated to demographic or lifestyle factors.”29

•Zinc (and copper) — When it comes to zinc, remember more is not better. In fact, it can backfire. When taking zinc, you also need to be mindful of maintaining a healthy zinc-to-copper ratio. Chris Masterjohn has a Ph.D. in nutritional sciences.30 He’s written about the relationship between zinc and copper, saying:31

“In one study, 300mg/day of zinc as two divided doses of 150 mg zinc sulfate decreased important markers of immune function, such as the ability of immune cells known as polymorphonuclear leukocytes to migrate toward and consume bacteria.

The most concerning effect in the context of COVID-19 is that it lowered the lymphocyte stimulation index 3-fold. This is a measure of the ability of T cells to increase their numbers in response to a perceived threat.

The reason this is so concerning in the context of COVID-19 is that poor outcomes are associated with low lymphocytes … the negative effect on lymphocyte proliferation found with 300 mg/day and the apparent safety in this regard of 150 mg/d suggests that the potential for hurting the immune system may begin somewhere between 150-300 mg/d.

It is quite possible that the harmful effect of 300 mg/d zinc on the lymphocyte stimulation index is mediated mostly or completely by induction of copper deficiency.

The negative effect of zinc on copper status has been shown with as little as 60 mg/d zinc. This intake lowers the activity of superoxide dismutase, an enzyme important to antioxidant defense and immune function that depends both on zinc and copper.

Notably, the maximum amount of zinc one could consume while staying in the acceptable range of zinc-to-copper ratios and also staying within the upper limit for copper is 150 mg/d.”

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