Zinc Supplements in COVID-19 Pathogenesis-Current Perspectives

Review Article

Austin J Nutr Metab. 2021; 8(2): 1107.

Zinc Supplements in COVID-19 Pathogenesis-Current Perspectives

Majeed M1,2, Chavez M2, Nagabhushanam K2 and Mundkur L1*

¹Sami-Sabinsa Group Limited, Bangalore 560 058, Karnataka, India

²Sabinsa Corporation, East Windsor, NJ 08520, USA

*Corresponding author: Lakshmi Mundkur, Sami-Sabinsa Group Limited, Peenya Industrial Area, Bangalore 560 058, Karnataka, India

Received: March 16, 2021; Accepted: April 26, 2021; Published: May 03, 2021


Zinc is an indispensable trace element required for several critical functions of the human body. Deficiencies of micronutrients can impair immune function and increase susceptibility to infectious disease. It is noteworthy that higher susceptibility to the SARS-CoV-2 viral infection is seen in individuals with micronutrient deficiencies and poorer overall nutrition. Research in the last two decades suggests that one-third of the global population may be deficient in zinc, which affects the health and well-being of individuals of all ages and gender. Zinc deficiency is now considered one of the factors associated with susceptibility to infection and the detrimental progression of COVID-19. The trace element is essential for immunocompetence and antiviral activity, rendering zinc supplements highly popular and widely consumed. Zinc supplements are required in small doses daily, and their absorption is affected by food rich in fiber and phytase. The organic forms of zinc such as picolinate, citrate, acetate, gluconate, and the monomethionine complexes are better absorbed and have biological effects at lower doses than inorganic salts. Considering the present global scenario, choosing the right zinc supplement is essential for maintaining good health. In the present review, we reexamine the role of zinc in immunity and antiviral activity and a comparative account of different forms of zinc supplements.

Keywords: Zinc; SARS-CoV-2; Zinc deficiency; Antiviral immunity; Supplements


Nutritional deficiency contributes to poor health and susceptibility to infection. The deficiency in micronutrients are not easily recognized as their manifestation is not very distinct and hence may not get noticed. Correcting the micronutriient deficiencies may be helpful in supporting the immune function and resist frequent infection, especially in the vulnerable population.

Zinc is only second to iron as an important trace element in the human body. It is abundantly distributed throughout body tissues and is vital for growth and development, gene expression, and immune functions [1,2]. Zinc is a structural component of nearly 2000 transcription factors and a required cofactor for more than 300 enzymes, which help in digestion, metabolism, and neuronal functions [2]. Numerous studies have shown that zinc is essential for maintaining a strong immune function, blood sugar levels and keeping skin, hair, eyes, and heart healthy [3]. Daily intake is required for maintaining the levels to support the essential biological functions as only 20-40% mineral is absorbed by the enterocytes in the gut, while the residual zinc is excreted [4]. Zinc may be stored in skeletal muscle and bone and a very small fraction (10-20 μM) is found circulating in the blood [5]. The prevalence of zinc deficiency is estimated to be 17-20% globally, predominant in African and Asian countries [6]. Zinc deficiency is commonly observed in the geriatric population, vegans/vegetarians, and individuals with chronic disease such as immunosuppression, Chronic Obstructive Pulmonary Disease (COPD), asthma, cardiovascular diseases, autoimmune diseases, kidney diseases, obesity, diabetes, liver disorders, inflammatory bowel disease and cancer, who are also known to be at high risk for SARS-CoV-2 infection [7,8]. Zinc is vital for a proper immune response as its deficiency results in defective lymphocyte responses, lymphopenia, and thymic atrophy [9]. In the present scenario of the pandemic viral infection, robust immunity is a major concern. In this review, we focus on the role of zinc in immunity and antiviral response, and the importance of zinc supplements in prophylaxis and treatment of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections.

Zinc in Respiratory Health: SARS-CoV-2 Infection

The world is now facing a serious pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), also known as the novel Coronavirus Disease 2019 (COVID-19). There is an urgent need for pharmacological, traditional, and complementary medicine approaches and nutritional intervention to aid in prevention, treatment, and recovery from the infection. SARSCoV- 2 is an enveloped beta coronavirus with a positive-sense singlestranded RNA genome [10]. It is transmitted via direct contact, respiratory secretions and remains stable on surfaces for days [11,12]. High morbidity has been observed among the elderly, especially those with prevailing chronic diseases [13]. The pathogenesis of COVID-19 is yet to be fully understood, but the multifactorial pathology results in a systemic hyperinflammatory response, cytokine storm, and an associated thromboembolic complication in severe cases [14,15].

Zinc, as a trace element, has potent antiviral and immunomodulatory properties [16]. It is used as a cofactor by different cellular proteins with immunomodulatory and antioxidant actions [17]. Zinc is essential for the development and activation of T-lymphocytes, which are the leading cells for defense against viral infections [18]. The antiviral property of zinc has been studied extensively in hepatitis C virus, coronavirus, human immunodeficiency virus and others [19].

Zinc is considered a potential supportive treatment due to its immune-modulatory and antiviral effect [16]. Hydroxychloroquine, a zinc ionophore, has been increasingly used as antiviral therapy for COVID-19 patients [21,22]. Further, zinc is known to improve antiviral immunity and diminish the risk of hyper-inflammation. The anti-oxidative effect of zinc could reduce lung damage and curtail secondary infections [22,23]. A significant number of COVID-19 patients were found to be zinc deficient compared to healthy individuals in a recent study. Severity and complications due to infection, were higher in zinc deficient patients, who had prolonged hospital stay associated with increased mortality [24].

Mechanism of Antiviral Activity of Zinc

Viral entry

The entry of infectious agents is prevented by the ciliary cells in mucosal layers. The coronavirus infection damages the ciliated epithelium and ciliary dyskinesia, thus impairing the mucociliary clearance [25]. Zinc could increase the ciliary beat frequency, the number, and the length of bronchial cilia, thus improving the elimination of virus particles and prevention of secondary bacterial infections [25]. Disruptions in the respiratory epithelial integrity facilitate the entry of the virus. Decreasing zinc level was found to increase the epithelial leakage in the respiratory tract in an ex vivo model of COPD, while lung integrity could be improved by zinc supplementation [26,27]. Zinc supplementation was shown to increase proteolysis of E-cadherin/beta-catenin and increase the expression of tight junction proteins like Claudin-1 and ZO-1, which improved lung integrity in a murine model of acute lung injury [27,28]. Further, zinc had an inhibitory effect on LFA-1/ICAM-1 interaction, which reduced leukocyte recruitment and inflammation in the respiratory tract, while high zinc levels improved the tolerance of the lung towards damage induced by mechanical ventilation [29,30].

SARS-CoV-2 infects cells expressing the surface receptors Angiotensin-Converting Enzyme 2 (ACE-2). Zinc binds to the active center of the ACE-2 active center and is thus essential for its enzymatic activity. The expression of ACE-2 expression is regulated by Sirt-1, which is downregulated by zinc. Thus, zinc is likely to have an indirect effect on ACE-2 expression and thus viral entry into the cell [31].

Viral replication

The antiviral effects of zinc have been demonstrated against several human viruses. Increasing the intracellular zinc concentration with zinc-ionophores like pyrithione was reported to impair viral replication in vitro [32,33]. Recent studies have shown the efficacy of chloroquine, a zinc ionophore, as an antiviral treatment for COVID-19 (20). Positive stranded RNA viruses use RNA-dependent polymerase for replication. Increased intracellular zinc ion concentrations was found to inhibit the viral replication by directly inhibiting the RNA polymerase activity in Vero cells [34]. Zinc could also interfere with the synthesis and assembly of viral proteins [35]. It was suggested that zinc plays a vital role in preventing viral fusion with the host membrane, decrease the viral polymerase function, impair protein translation and processing, block viral particle release, and destabilize the viral envelope in different viral models [34,36,37]. Zinc was also reported to act in a synergistic manner with standard antiviral therapy [38]. Overexpression of metallothionines was also reported to inhibit replicating few viruses such as flaviviruses and encephalitis virus. Metallothionines are hypothesized to sequester Zn2+ away from the viral proteins by acting as zinc chaperones and facilitating antiviral signaling [39].

Zinc and Immune Response

Zinc is crucial for the proper folding and activity of various cellular enzymes and transcription factors. It is a component of the thymic hormone and thus mediates the normal development and function of innate immune response cells, neutrophils, and natural killer cells [38]. Zinc deficiency suppresses human immunity by affecting T-helper cells and the balance of the helper T cell (Th1 and Th2) functions, antibody response, activity of natural killer cells and macrophages [40,41]. Supplementation with zinc could activate the interleukin -2 expression and normalize the cellular immune response in elderly individuals and reduce mortality from infections [42,43]. Apart from improving immune response, zinc is known to play an important role in maintaining immune tolerance. It induces regulatory cell differentiation while dampening the proinflammatory Th17 and Th9 differentiation [44-46]. Thus, zinc supplements improve the T cell function, thereby strengthening the cell-mediated immunity [47]. Zinc also enhances the phagocytosis, intracellular killing, and cytokine production in macrophages [47]. In elderly population, zinc supplementation is believed to help to manage immune senescence [48]. Zinc deficiency is associated with higher susceptibility to infections, which could be reversed with supplementation. Hepatitis and human papilloma virus-infected individuals showed an enhanced response to antiviral therapies when supplemented with zinc [49,50].

Zinc and antiviral immunity

Zinc was shown to induce the production of antiviral interferons (IFN-a and IFN-γ) in leukocytes and reduce the release of proinflammatory cytokine, TNF-a [51]. Zinc supplementation in the elderly restored the production of IFN-a [52]. Imbalance in the immune response is a hallmark of SARS-CoV-2 infection. Heightened cytokine release increases reactive oxygen and nitrogen species (ROS and RNS), and hyperactive immune cells in the lungs complicate the disease, leading to lung tissue destruction, systemic inflammation, and organ failure [53]. This leads to the development of Acute Respiratory Distress Syndrome (ARDS) in patients, accompanied by fluid accumulation in the lungs, interstitial edema with severely limited oxygen exchange [54]. Elevated levels of proinflammatory mediators, increased ROS levels reversible by zinc supplementation [27,55]. COVID-19 patients show increased expression T cell exhaustion markers like Tim-3 and PD-1 and neutrophilia and lymphopenia, associated with poor prognosis of these patients [56,57]. Zinc is required for the development and function of lymphocytes and its supplementation can reverse lymphopenia [58,59]. In the recovery phase of COVID-19 patients an increase of CD14+ monocytes and NK cells could be correlated with clinical improvement [60]. These CD14+ cells require sufficient intracellular zinc levels for phagocytic activity and inflammatory response [9], while zinc supplementation increased the cytotoxicity of NK cells and cytotoxic T cells toward their target cells [61]. These studies suggest that zinc balances immune response by influencing several cellular pathways.

Zinc supplementation in viral infections

Several studies showed reduced symptom severity, frequency, and duration of common cold after zinc supplementation. Higher susceptibility to infections associated with zinc deficiency could be reversed with supplementation. Further, zinc supplementation enhanced the response to antiviral therapies in hepatitis and human papilloma virus-infected individuals [49,50]. In patients with human immunodeficiency virus (HIV) infections, zinc supplementation was found to increase the peripheral CD4+ T cells [62]. An increase in zinc deficiency with age increases the susceptibility of older individuals to viral infections. Elderly subjects supplemented with 45 mg elemental zinc/day for a year, demonstrated a remarkable reduction in the incidence of infection and plasma oxidative stress markers [58]. Zinc supplementation enhanced the NK cell cytotoxicity in both healthy and zinc deficient elderly individuals [63,64], and increased the peripheral CD4+ T cells in HIV patients [42]. A systematic metaanalysis showed that zinc consumed as gluconate lozenges reduce the first signs of cold duration and severity [65,66]. Few clinical studies in the last two decades are listed in Table 1.