James Odell, OMD, ND, L.Ac.
The significance of the immune system is largely overlooked, and most people do not think about it unless problems occur. Coronavirus infection has made millions of people think about their immune system and how to keep it strong. The good thing is that there are many things that can be done to improve the immune system’s functions, and one of them is supplementation with zinc.
Zinc (Zn), the second most abundant trace metal in the human body after iron, is essential for multiple cellular functions including maintenance of immune health. Zn plays pivotal roles in cellular integrity and biological functions related to cell division, growth, and development that possess potent immunoregulatory and antiviral properties.1, 2 It acts as a cofactor for many enzymes and proteins involved in antioxidant, anti-inflammatory, and apoptotic effects.3
Studies have shown that around 10% of our body proteins utilize zinc and that Zn is a cofactor in at least 200 immunomodulatory and antioxidant reactions. Additionally, more than 300 enzymes are dependent upon zinc for their metabolic activity. The International Union of Biochemistry discovered six categories of enzymes including hydrolases, isomerases, ligases, lyases, oxidoreductases, and transferases in which zinc is a basic component of the catalytic site/sites of at least one enzyme in each group.4, 5 Enzymes that use zinc as a cofactor are known as metalloenzymes. Many of these Zn dependent enzymes are critical for the immune system to function. An example is the zinc dependent enzyme thymulin, that stimulates the development of T-cell lymphocytes within the thymus gland.
Zinc also functions as an antioxidant and can stabilize membranes. As an antioxidant, it protects cells from the damaging effects of oxygen radicals generated during immune activation.6, 7, 8 Zinc is also a cofactor for the antioxidant enzyme superoxide dismutase that converts superoxide to hydrogen peroxide, as shown below.
Zinc is present in the body almost exclusively as Zn2+ (a divalent metal cation) bound to cellular proteins. Approximately 70% of circulating zinc is bound to serum albumin (a plasma protein).Factors or conditions affecting this serum albumin concentration can, in turn, affect serum zinc levels. The availability of serum Zn is sensitive to the amounts of Zn absorbed from the diet and a reasonably constant dietary supply is thought to be necessary to satisfy the normal requirements of Zn for maintenance and growth. Serum zinc has a rapid turnover to meet tissue demands.
Zinc has a high affinity for electrons, enabling interactions with several amino acid side chains. Interactions, especially with sulfur and nitrogen atoms in the amino acids cysteine and histidine, respectively, enable zinc to crosslink remote regions within and between polypeptides to modify protein structure and function. Given this ability, its relative nontoxicity, and the fact that it does not engage in damaging redox reactions, zinc is ideally suited to play a central role in intracellular metabolism.9
Zinc Supplementation for Viral Diseases
During the last several decades, numerous studies have shown that Zn supplementation can improve the outcome of many inflammatory and degenerative diseases. It has recently been demonstrated that Zn possesses a variety of direct and indirect antiviral properties, which are realized through different mechanisms. Administration of Zn supplement has the potential to enhance antiviral immunity, both innate and humoral, and to restore depleted immune cell function or to improve normal immune cell function. The effectiveness of Zn against several pathogenic viral species is mainly realized through physical processes, such as virus attachment, infection, and uncoating. Zn may also protect or stabilize the cell membrane which could contribute to blocking the virus entry into the cell. On the other hand, it was demonstrated that Zn may inhibit viral replication by alteration of the proteolytic processing of replicase polyproteins and RNA-dependent RNA polymerase in rhinoviruses, HCV, and influenza virus, and diminish the RNA-synthesizing activity of Nidoviruses, for which coronaviruses (SARS-CoV-2) belongs.10
Antiviral properties of Zn against several viral species occur through processes (repeated above) as well as through inhibition of viral protease and polymerase enzymatic processes. Zn may interfere with the proteolytic processing of viral polyprotein by its direct actions on the viral protease (as in picornavirus, encephalomyocarditis virus, and poliovirus) and alteration of the tertiary structure (as an encephalomyocarditis virus).11, 12
Zinc and Immunity
Zinc has been shown to play an all-important role in the regulation of the immune response, particularly T cell‐mediated function.13, 14, 15 Immune response led by interferons and cytotoxic T lymphocytes are invariably required to clear viral infections. Zinc ions (Zn2+) are closely involved in the normal development, differentiation, and function of immune cells, thus considered critical for generating both innate and acquired (humoral) antiviral responses.16
Zinc Deficiency and Immunity
Mild to moderate zinc deficiency is common worldwide, as was shown over 30 years ago.17 This deficiency in humans has escalated over the last three decades due to commercial agriculture depleting the soil of micronutrients. Notably, zinc deficiency/insufficiency is prevalent in populations aged over 71 years18, 19, 20, 21, 21, in people with chronic diseases23, 24, 25, including diabetes26, 27, 28, and cardiovascular diseases29, 30, and hospitalized patients following stroke.31
In persons suffering from marginal zinc deficiency, clinical signs are depressed immunity, impaired taste and smell, the onset of night blindness, impairment of memory, and decreased spermatogenesis in males.32, 33 Severe zinc deficiency is characterized by severely depressed immune function, frequent infections, bullous pustular dermatitis, diarrhea, alopecia, and mental disturbances.34
Importantly, zinc‐deficient subjects present with greater susceptibility to a variety of pathogens.35 Thus, Zn deficiency is associated with increased susceptibility to infectious diseases caused by bacterial, viral, and fungal pathogens, and may be caused by some other diseases (e.g., liver cirrhosis or inflammatory bowel disease), aging, and lifestyle-associated factors.36, 37
Zn deficiency impinges on the survival of immune cells and adversely affects important functions such as phagocytosis, target cell killing, and cytokine production. Studies show that Zn deficiency plays a role in the thymus and lymphoid tissue atrophy38 and declines in the mechanisms of activation of both helper T cell39 and cytotoxic CD8+ T cell responses.40 Specifically, Zn deficiency leads to a compromised immune system, as evidenced by degeneration of thymus, lymphopenia, and defective lymphocyte responses.41, 42, 43
Zn deficiency may also cause immunodeficiency with severe lymphopenia that is characterized in part by a considerable decrease in developing B cell compartments in the bone marrow.44, 45 Moreover, Zn potentiates the interferon (IFN)-α effect by an order of magnitude which can be used to counteract IFN antagonism by SARS-CoV-2 proteins.46
Thus, appropriate administration of Zn supplement in adequate therapeutic doses has the potential either to restore depleted immune cell function or to improve normal immune cell function. It may also act synergistically when co-administered with other anti-infective therapies, such as certain traditional Chinese medicinal herbal formulations, and the drugs ivermectin and hydroxychloroquine.
It has been shown that a significant number of hospitalized COVID-19 patients were zinc deficient and that these zinc-deficient patients developed more complications, and the deficiency was associated with a prolonged hospital stay and increased mortality.47, 48, 49
Zinc Supplementation for SARS-CoV-2 Prophylaxis and Infections
Currently, evidence is mounting that zinc may potentially reduce the risk, duration, and severity of SARS-CoV-2 infections, particularly for populations at risk of zinc deficiency, including people with chronic disease co-morbidities and older adults.50, 51, 52, 53, 54, 55
One of the hallmarks of SARS-2 coronavirus infection is an imbalanced immune response. With early treatment, most symptomatic individuals recover without hospitalization. However, in the aged and those with comorbidities who are without early treatment, an inflammatory process may ensue. Due to hyper-inflammation, immune products including pro-inflammatory cytokines like interleukin (IL)-6, C-reactive protein, tumor necrosis factor (TNF)α and IL-1β (often referred to as a ‘cytokine storm’), reactive oxygen, and nitrogen species in connection with the recruitment of high numbers of strongly activated immune cells to the lungs. A cytokine storm, also termed macrophage activation syndrome, is a potentially fatal systemic hyperinflammation associated with hypercytokinaemia and multiple organ failure. This process destroys tissue, particularly causing lung damage and organ failure, while the body’s anti-inflammatory response remains insufficient.
Thus, there is a pressing need to focus on identifying and correcting deficits in immune function to reduce the risk of severe progress of SARS-CoV-2 infections and to use nutrients such as vitamin D3, vitamin C and zinc to enhance immunity. Thus, current efforts are being aimed at supporting immunity with nutrients and Zn supplementation, therefore correcting a loss of Zn secondary to the disease, while restoring the zinc-dependent functions of the immune system.56, 57
The Need for Zinc Ionophores
One major barrier to zinc treatment is that zinc has a hard time passing through the cell’s membrane which is made of fat. Fortunately, some molecules can act as facilitators and enhance the entry of zinc into the cell. These are known as zinc ionophores. The definition of an ionophore is, “a substance which is able to transport particular ions, like zinc, across a lipid membrane in a cell”. Technically, ionophores are molecules forming complexes with ions and facilitate ion transport across lipid bilayers. There are ionophores promoting transport of cations (cationophores) and anion (anionophores), but the latter are less common. Remembering, Zn is present in the body almost exclusively as Zn2+ a divalent metal cation. Cationic ionophores may transfer proton, alkali, alkaline earth, or transition metal ions like zinc. Dietary plant polyphenols such as the flavonoids quercetin and epigallocatechin-gallate (EGCG – green tea extract) act as antioxidants and are excellent ionophores of zinc. Remarkably, the activities of numerous enzymes that are targeted by polyphenols are dependent on zinc. Thus, these polyphenols chelate zinc cations, and act as zinc ionophores, transporting zinc cations through the plasma membrane.
1. Zinc ions (blue hexagons) are in solution outside the cell.
2. The cell’s membrane and binding molecules limit the ability of zinc to penetrate the cell cytoplasm via special ports (light green shape).
3. A zinc ionophore (red triangle) activates the port (dark green shape) to allow zinc to enter the cell
4. Once in the cell, zinc is then able to block the enzyme RNA-dependent RNA polymerase (black shape), which turns off viral replication.
We know Zn impairs replication of RNA viruses such as SARS-CoV-1 and is shown clinically effective against SARS-CoV-2. However, to achieve adequate intracellular zinc levels, administration with an ionophore, which increases intracellular zinc levels, is often necessary.58
It has been shown that increasing the intracellular Zn concentration with zinc-ionophores can efficiently impair the replication of a variety of RNA viruses, including coronaviruses, poliovirus, and influenza viruses.59 Particularly, hydroxychloroquine, a drug being repurposed for COVID-19, is a well-known zinc ionophore which transports zinc to lysosomes inside the cell. Ivermectin may also contribute to increased intracellular zinc.60 Combined treatment with an ionophore and zinc is necessary in order to substantially increase the level of zinc inside a cell.
Zinc Dosage
Unlike iron, the body has no specialized zinc storage system, which means it is recommended to supplement zinc daily if used as a prophylactic or therapeutic mineral. According to the National Institutes of Health Office of Dietary Supplements, it takes just 11 milligrams of zinc to maintain its optimal role in cellular metabolism.61 Unfortunately, many diets are completely void of zinc and most cannot obtain more than 17 mg from even the best diet. On the lower end, some clinicians recommend 20 mg per day of zinc per day for adults. On the higher end, as in the Dr. Valdimir Zelenko protocol includes 240 mg per day.62
The Recommended Dietary Allowance (RDA) for zinc is 8 mg for women and 11 mg for men. That is not a therapeutic level, but the level the body needs to survive. An upper long-term safe level for an adult would be around 25 to 50mg daily. Like all supplements and drugs, dosage should be individually tailored. Zinc comes in many forms:
Zinc gluconate: As one of the most common over-the-counter forms of zinc, zinc gluconate is often used in cold remedies, such as lozenges and nasal sprays.
Zinc acetate: Like zinc gluconate, zinc acetate is often added to cold lozenges to reduce symptoms and speed up the rate of recovery.
Zinc sulfate: In addition to helping prevent zinc deficiency, zinc sulfate has been shown to reduce the severity of acne. This is the form Dr. Zelenko recommends in his COVID protocol.
Zinc picolinate: Some research suggests that your body may absorb this form better than other types of zinc, including zinc gluconate and zinc citrate.
Zinc orotate: This form is bound to orotic acid and is one of the most common types of zinc supplements on the market.
Zinc citrate: This form is as well-absorbed as zinc gluconate but has a less bitter, more appealing taste.
Available in capsule, tablet, and lozenge form, there are plenty of options to get your daily dose of zinc — regardless of the type you choose.
Zinc Toxicity
Zinc is relatively nontoxic, particularly if taken orally. Zn toxicity is rare, but long-term high dose zinc supplementation can lead to copper deficiency as zinc can displace copper from certain proteins and enzymes. Zn reduces the amount of copper the body absorbs because copper competes with zinc to bind with metallothionein, the binding protein that brings zinc into the intestinal cells. Excess copper can also deplete Zn. Thus, the ratio of zinc: copper is arguably more important than the concentration of either copper or zinc, and a common problem is excessive copper in water from copper pipes or copper cookware. Additionally, manifestations of overt toxicity symptoms (nausea, vomiting, epigastric pain, lethargy, and fatigue) may occur with extremely high zinc intakes. Based on the current knowledge of beneficial vs. harmful effects of Zn, it can be safely concluded that the risk to reward ratio is in favor of Zn supplementation in COVID-19.
Source: Pal, Amit, Rosanna Squitti, Mario Picozza, Anil Pawar, Mauro Rongioletti, Atanu Kumar Dutta, Sibasish Sahoo, Kalyan Goswami, Praveen Sharma, and Rajendra Prasad. "Zinc and COVID-19: basis of current clinical trials." Biological Trace Element Research 199, no. 8 (2021): 2882-2892.
Conclusion
One of the most important roles of zinc is to maintain a healthy immune system and thereby help the body to fight off a range of infections, including influenza and coronaviruses. Evidence from numerous systematic reviews has found zinc supplementation effective for the prevention of acute respiratory infections in young children and adults. Zinc has been shown to inhibit the growth of several viruses in vitro.
The effects of zinc on these key immunologic mediators are rooted in the myriad of roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Zinc affects multiple aspects of the immune system including both non-specific, and specific, immunity. Non-specific immunity includes the barrier function of the skin and the mucous membrane linings of the gastrointestinal and respiratory tracts, polymorphonuclear leukocyte function, natural killer cell function, and complement activity. Effects on specific immunity include lymphocyte activation, particularly T- and B-lymphocyte functions, and antibody production. The macrophage, a fundamental cell in many immunologic functions, is adversely affected by zinc deficiency, which can lead to dysregulation of intracellular viral killing and decreased white cell phagocytosis.
Zinc supplementation strengthens the integrity of the lung epithelium, decreases viral replication, preserves antiviral immunity, attenuates the risk of hyper-inflammation, supports antioxidative effects, and thus reduces lung damage, and minimizes secondary infections. Furthermore, zinc improves antiviral immunity and ameliorates tissue damage caused by inflammation in critical COVID-19 patients. Especially older subjects, those with co-morbidities and chronic diseases would most likely benefit from prophylactic and therapeutic zinc supplementation together with an ionophore.
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Correspondence from Dr Vladimir Zelenko on Treatment of COVID-19 in New York (google.com)