_____________________________________________________________________________________________________ *Corresponding author: E-mail: akibul433@gmail.com; Asian Journal of Immunology 3(1): 269-277, 2020; Article no.AJI.58128 Role and Effects of Micronutrients Supplementation in Immune System and SARS-Cov-2(COVID-19) Akibul Islam Chowdhury1* 1 Department of Food Technology and Nutrition Science, Noakhali Science and Technology University, Sonapur-3814, Bangladesh. Author’s contribution The sole author designed, analyzed and interpreted and prepared the manuscript. Article Information Editor(s): (1) Dr. Tania Mara Pinto Dabés Guimarães, Federal University of Minas Gerais, Brazil. Reviewers: (1) Ghada Mostafa Lofty El Ashy, Egypt. (2) Ritu Ghosh, Rabindranath Tagore University, India. (3) Hanchu Dai, University of Illinois, USA. Complete Peer review History: http://www.sdiarticle4.com/review-history/58128 Received 31 May 2020 Accepted 21 June 2020 Published 30 June 2020 ABSTRACT COVID-19 is a serious disease caused by the virus SARS-CoV-2 which is easily transmitted to humans. There are no vaccines or drugs discovered yet to control its transmission and prevent the disease. In that case, it is important to find the methods of preventing and controlling it. To fight against the virus a well-functioning immune system is necessary. The immune system is always active but if an individual becomes infected then the activity of immune system is enhanced to fight against the virus and recover the body from infection. Adequate intake of micronutrients through diet (vitamins A, B-complex, C, D and zinc, selenium, copper, iron) can help to boost up the immune system as each of the nutrients named above has roles in supporting antiviral and antibacterial defense. Although the supplementation of micronutrients can be given, it is necessary to provide the right amount of supplements after assessing the nutritional status of each individual as supplementation of micronutrient have some adverse effects. Therefore, it is recommended to follow a healthy diet to prevent COVID-19 and also assess the nutritional status of COVID-19 patients before prescribing treatments. Keywords: Micronutrients; immune system; micronutrient supplementation; respiratory tract infection; SARS-CoV-2; COVID-19. Review Article Chowdhury; AJI, 3(1): 269-277, 2020; Article no.AJI.58128 270 ABBREVIATIONS IL : Interleukin CD : Cluster of Differentiation COVID-19 : Corona Virus Disease 2019 SARS CoV-2 :Severe Acute Respiratory Syndrome WHO : World Health Organization PMNL : Polymorphonuclear Leukocytes DTH : Delayed-Type Hypersensitivity 1. INTRODUCTION COVID-19, a severe acute respiratory syndrome is caused by the virus SARS-CoV-2 and WHO declared this as a global pandemic [1]. Previous epidemics related to CoV included that severe acute respiratory syndrome (SARS)-CoV was started in China in 2002 [2] and the Middle East respiratory syndrome (MERS)-CoV in the Middle East, first reported in 2012 [3]. Not all types of people are suffering from this virus. People with weak immune system are much exposed to SAS- Cov-2 [4]. There are many recommendations to prevent the spread of COVID-19 from the WHO [5], the UK [6], USA [7] governments and the European Commission [8] as well as public health agencies including the key direction of self-isolation [9]. Some potential treatment options (anti-viral, anti-malarial, herbals) are also introduced to treat COVID-19 patients [10]. Nutrition especially micronutrients play a vital role to alleviate both mortality and morbidity in COVID-19 as micronutrients boost up our immunity system. Nutritional status is an important factor influencing the outcome of patients with COVID-19 [11]. In a study, a list of nutrients were identified with possible anticoronavirus effects based on in vitro and clinical studies [11]. Several micronutrients have antioxidants feature such as Vitamin C, Vitamin E, and beta-carotene. Antioxidants increase response to influenza virus vaccine compared with placebo and also increase the number of T- cell subsets, enhance lymphocyte response to mitogen [12]. The activity of the immune system in our body is accompanied by an increasing rate of metabolism, requiring energy sources, substrates for biosynthesis, and regulatory molecules that are derived from the diet. Adequate supply of essential nutrients is required in this pandemic situation [13,14]. This review is based on published data and information and major searches were done using Google scholar and PubMed. This review aims to describe the role of specific micronutrients in supporting the immune system and also describes the effect of micronutrients supplementation in this pandemic situation. 2. ROLE OF IMMUNITY IN VIRAL INFECTION When an individual exposed to viral infection, the immunity system becomes vital. First of all, the innate immunity system of the body such as macrophages, monocytes and dendritic cells recognize the foreign particles or pathogens. The presence of pattern recognition receptors (PRRs) and microbe-associated molecular patterns (MAMPs) help in the identification of the pathogens. TLR7 and TLR8 of innate immune system are more important for recognition of corona virus. After viral infection some cells release IFN-α and IFN-β. Natural killer cells are directly activated after viral infection to kill the infected cells. The maturation of dendritic cells is induced by PRRs signaling which functions to precess and present viral antigen. The presentation of viral antigens is resulted by upregulation of MHC I on virally infected cells which kill the virally affected cells releasing the pore forming protein like perforin. The production of IL-2 by CD4+ helper T lymphocytes and T helper 1 phenotype promotes cytotoxic T lymphocytes activity which produce antival antibodies by the differentiation of B lymphocytes to plasma cells. Then these antibodies can bind to the viruses and destroy them [15-18]. 3. ROLE OF VITAMIN A IN IMMUNITY The roles of vitamin A in the immunity system and host susceptibility to infection are identified in many studies [19-23]. The main functions of vitamin A are helping in visions, providing immunity, contributing in gene expression, etc. Vitamin A is required for immune cell maturation and functioning as boosting the immune system is the main focus to prevent the spread of COVID-19. Deficiency of vitamin A may impair barrier functions and immune response. Vitamin A and its metabolites help to modulate innate immunity along with barrier function and also control neutrophil maturation. The functions of neutrophil are to ingest and kill bacteria. Vitamin A also supports in phagocytic activity to promote bacteria killing. Vitamin A helps to increase the activity of natural killer cells which have antiviral defenses. Other functions of vitamin A are to control dendritic cell, CD4+ T lymphocyte maturation and maintaining the balance between T helper 1 and T helper 2 lymphocytes. There are various chemical forms of vitamin A and each Chowdhury; AJI, 3(1): 269-277, 2020; Article no.AJI.58128 271 of the form has different activity in immune system. Movements of T lymphocyte to the gut- associated lymphoid tissue is promoted by retinoic acid and it is also required for CD8+ T lymphocyte survival and proliferation [24]. Many systemic reviews supported that vitamin A could reduce the rate of mortality and mobility from measles and improved symptoms in acute pneumonia. A systemic review study is conducted by Imdad et al. [25] found that vitamin A decreased all causes of mortality and morbidity from diarrhea and measles and decreased the incidence of diarrhea and measles. Another study found that vitamin A decreased morbidity and mortality with pneumonia and also increased the clinical response and shortened length of hospital stay [26]. Common sources of vitamin A are Liver, eggs, oily fish, fortified margarine, dairy products, carrots, orange fruits, green and yellow vegetables and tomato juice and the recommendation of vitamin A intake for adults is 3000-5000IU [27]. The adverse effects of vitamin A supplementation are identified in Table 2. 4. ROLE OF VITAMIN D IN IMMUNITY Vitamin D is an important micronutrient for health because of its function in bone, immune etc. Several studies included the role of vitamin D in immune system [28-30]. The active form of vitamin D is 1, 25-dihydroxyvitamin D3 which has important immune-regulatory properties. However, the functions of vitamin D on the cellular components of immunity are rather complex. Vitamin D improves antimicrobial peptide synthesis in epithelial tissue [31] and also inhibits the proliferation of T cell, and production of cytokines by T helper 1 lymphocyte. It also has little impact on CD8+ T lymphocyte. Low level of vitamin D in the body has been associated with upper respiratory tract infections [32,33] including influenza [34], chronic obstructive pulmonary disease [35] and allergic asthma [36]. Many studies showed that supplementation of vitamin D can reduce the risk of viral respiratory tract infection [37] and many meta-analysis studies have been concluded this subjects. According to Bergman et al. and Martineau et al., vitamin D decreases the risk of respiratory tract infections [38,39]. A systematic review and meta-analysis conducted by Zhou et al. [40] concluded that risk of pneumonia had been increased with deficiency of vitamin D. So, vitamin D can be important micronutrients to treat COVID-19 patients. The common sources of vitamin D are sunlight, Liver, eggs, oily fish, fortified margarine and dairy products and recommendation of vitamin D intake for adults is 400-1000IU [27]. The adverse effects of vitamin D supplementation are identified in Table 2. Table 1. Effects of vitamin and mineral supplementation on immunity Immune system Vitamins and minerals Models Effects Macrophages C supplementation [41] Human Stimulation of chemotaxis and phagocytosis E dietary supplementation [42] Rat Inhibited glomerular sclerosis Zinc supplementation [43] human Increased IL-1, IL-6, TNF-α, INF-γ Natural killer cell C dietary supplementation [44] Human Enhance activity E dietary supplementation [45] Human Enhance activity Zinc [46] Human Enhance activity Selenium [47] Mouse Enhance activity and IL-2 protein Iron [48] Mouse Decreased activity PMNL B12 supplementation [49] Human Increased bacterial killing C supplementation [50] Human Enhanced phagocytosis, decreased superoxide production C,E supplementation [51] Human Suppressed production of oxygen free radical Copper, Zinc and Iron supplementation [52-54] Human Increased neutrophil function DTH C supplementation [55] Human Increased E supplementation [56] Human Increased T cell C, E and A supplementation [57] Human Increased Zinc supplementation [58] Human Increased T lymphocyte Abbreviations: PMNL: Polymorphonuclear Leukocytes, DTH: Delayed-Type Hypersensitivity Chowdhury; AJI, 3(1): 269-277, 2020; Article no.AJI.58128 272 Table 2. Adverse effects of vitamin and mineral supplementation [27,59-61] Vitamin and minerals Adverse effects associated with supplements Vitamin A Hepatotoxic effects, visual change, hair and skin change, risk of lung cancer among smokers, diarrhea Vitamin B6 Sensory neuropathy, ataxia Vitamin B12 No upper limit unknown Vitamin D Hypocalcaemia, soft tissue calcifation Vitamin C Diarrhea, gastric Vitamin E Nausea, vomiting, diarrhea, headache, fatigue, blurred vision Zinc Nausea and vomiting, immune-suppression and impaired copper uptake Selenium Brittle hair and nails, peripheral neuropathies and gastrointestinal upset Iron Nausea, vomiting, reduced zinc uptake and constipation 5. ROLE OF VITAMIN C IN IMMUNITY Vitamin C is a water soluble vitamin which has antioxidant properties. It plays a major role in the immune system of the human body. It is required for collagen biosynthesis and also helps in the migration of leucocytes to the sites of infection [62]. Other roles of vitamin C in immunity are phagocytosis, bacteria killing, and natural killer cells activity [62,63]. Vitamin C supplementation enhances the activity of natural killer cells [44]. Variety of studies stated that the severity of upper respiratory tract infections can be lowered by vitamin C supplementation. A meta-analysis stated that vitamin C decreased the incidence of pneumonia as well as reduced severity and morbidity from pneumonia [64]. For its functional properties, many doctors and researchers suggested to increase the intake of vitamin C to boost up the immunity and to fight against the corona virus. The common sources of vitamin C are Citrus fruits, broccoli, kiwi, yams, strawberries, melons and recommendation of vitamin C intake for adults is 60-90mg [27]. The adverse effects of vitamin C supplementation are identified in Table 2. 6. ROLE OF VITAMIN B-COMPLEX IN IMMUNITY B vitamins are mainly involved in intestinal immune regulation and help in the gut-barrier functions. Folic acid increases the number of circulating T lymphocyte, but the activity of neutrophils appears unchanged. Vitamin B12 increases the phagocytic and bacteria killing capacity of neutrophils while vitamin B6 helps in the lymphocyte proliferation and increases the number of T lymphocyte in the blood. Folic acid, vitamin B6 and B12 enhanced the activity of natural killer cells which would be important in antiviral defense [65,66]. A study found that deficiency of vitamin B6 decreased the T lymphocyte and B lymphocyte proliferation and IL-2 production [67]. The common sources of vitamin B complex are Poultry, fish, meat, nuts, legumes, whole grains, potatoes, meat, egg, seaweed etc and the recommendation of vitamin B6 and B12 for adults are 1.3-2 mg and 2.4-6 μg respectively [27]. The adverse effects of vitamin B complex supplementation are identified in Table 2. 7. ROLE OF VITAMIN E IN IMMUNITY Vitamin E acts as a scavenger of free radical by blocking the per-oxidation of polyunsaturated fatty acids (PUFA) and also acts as antioxidants. It is suggested that vitamin E is an important nutrient in the immune system [68]. Due to vitamin E deficiency, T-cell mitogenesis, IL-2 production, PMN phagocytosis, and PMN chemotaxis are decreased [56]. It is found that there is a positive association between vitamin E and cell-mediated immune responses and vitamin E supplementation appears to be beneficial for adults people [69]. Vitamin E supplementation also enhances the activity of helper T lymphocyte and improves vaccine responses [70]. Several studies identified that vitamin E supplementation reduced the risk of respiratory tract infections and decreased the duration of respiratory tract infections among adults [71]. The common sources of vitamin E are Plant oils (soya, corn, olive), nuts, seeds, wheat germ and the recommendation of vitamin E for adults people is 15-20 mg [27]. Supplementation of vitamin E also has some adverse effects which are identified in Table 2. 8. ROLE OF ZINC IN IMMUNITY In this COVID-19 situation, zinc is considered as a supportive treatment therapy as it has direct antiviral effects [72]. It is found that zinc supplementation may have positive effects in the Chowdhury; AJI, 3(1): 269-277, 2020; Article no.AJI.58128 273 treatment of COVID-19 patient [73]. The role of zinc in immunity is explained in many studies [74-76]. Zinc deficiency can cause loss of T helper cells and also responsible for atrophy of thymus and spleen. Zinc increases the IgM plaque response and IgG response. Cell mediated immunity is also increased with zinc supplementation. T lymphocyte proliferation is also maintained by proper dietary intake of zinc [77]. Some meta-analysis found that zinc decreased the prevalence and incidences of pneumonia as well as duration of common cold [78,79]. The common sources of zinc are meat, cheese, cereals and grains, shellfish etc. 9. ROLE OF SELENIUM IN IMMUNITY Selenium has important effect on both innate and acquired immunity. Selenium enhances the function of T lymphocyte and B lymphocyte and also increases the activity of natural killer cell [80,81]. A study found that selenium supplementation improved immune function in the human body [82]. The common sources of selenium are fish, meat, egg and nuts. Supplementation of selenium also has some adverse effects on the body. 10. ROLE OF COPPER IN IMMUNITY Some studies described the importance of copper in the immune system. Copper has antimicrobial properties, and also increases the activity of natural killer cell and neutrophils, monocyte function [83,84]. Some studies showed that lymphocyte proliferation and IL-2 production are promoted by copper [85]. A systematic review found that respiratory tract infection can be reduced by copper supplementation [86]. The common sources of copper are nuts, shellfish and some vegetables. 11. CONCLUSION Nutrition is very important for every steps of life and proper intake of both micronutrients and macronutrients can help to prevent and treat several infectious diseases. All nutrients named above have special role in immune system of the body, and consumption of adequate amount nutrients is necessary to boost up our immune function. Immune system can also be boosted up by supplementation of these nutrients. However, there are some adverse effects of micronutrients supplementation in case of overdosing. Many studies showed both positive and negative effects of micronutrients supplementation on immune response and human health. 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Scandinavian Journal of Clinical and Laboratory Investigation. 2014;74(7): 561-7. _________________________________________________________________________________ © 2020 Chowdhury; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Peer-review history: The peer review history for this paper can be accessed here: http://www.sdiarticle4.com/review-history/58128 http://creativecommons.org/licenses/by/4.0