Micronutrients and bioactive compounds in the immunological pathways related to SARS-CoV-2 (adults and elderly).

The new coronavirus pandemic is affecting the entire world with more than 25 million confirmed cases in August 2020 according to the World Health Organization. It is known that the virus can affect several tissues and can progress to a respiratory failure in severe cases. To prevent the progression to this stage of the disease and minimize all the damage caused by coronavirus (SARS-CoV-2) the immune system must be in its integrity. A healthy nutritional status are fundamental to efficient immunological protection and consequently a good response to SARS-CoV-2. Micronutrients and bioactive compounds perform functions in immune cells that are extremely essential to stop SARS-CoV-2. Their adequate consumption is part of a non-pharmacological intervention to keep the immune system functioning. This review has as main objective to inform how micronutrients and bioactive compounds could act in the essential immunological pathways could stop SARS-CoV-2, focusing on the functions that have already established in the literature and transposing to this scenario.

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the new coronavirus pandemic, named by the World Health Organization (WHO) as coronavirus disease 2019 (COVID-19) has reached almost all countries or territories worldwide, with more than 25 million confirmed cases and more than 800 thousand deaths according to data published on the WHO website at August 31, 2020 [1]. The SARS-CoV-2 is an enveloped virus, nonsegmented, with a simple RNA strand, a phospholipid bilayer covered by “spike” glycoproteins, and its pathogenesis being studied by several researchers [2]. Figure 1 represents a schematic of the main structural components of the virus.

Fig. 1

Structural scheme of the SARS-CoV-2.

Adapted from Li et al. [2]

Although the pathophysiological mechanisms associated with COVID 19 are not fully elucidated, Guan WJ and colleagues showed that not all people exposed to the SARS-Cov-2 will be infected and not all those infected will develop the most severe symptoms [3]. Based on that, the infected subject can be classified into three distinct stages, according to the symptoms and presence of the virus [4]. Stage 1 is related to the virus's incubation period, which can be detected or not, and with the absence of COVID-19′s symptoms as well. Stage 2 is the period when the virus can be detected and there are mild symptoms. Lastly, stage 3 represents the period that the subject has a high viral load and severe respiratory symptoms [4]. Besides the respiratory system, SARS-CoV-2 induced functional impairment was observed in the, nervous, cardiovascular and gastrointestinal systems [5, 6]. Once the integrity of the human immune system (IS) has a pivotal role to protect the body against the severity of the symptoms in the different systems the appropriate immune response (IR) is extremely necessary to control or to minimize the effects of the viral infection [2].

A healthy nutritional status are fundamental to efficient immunological protection. To ensure the IS functionality, the ideal contribution of macro and micronutrients should be taken into account [7, 8]. It has already been well established that during infection-induced energy demand increases, the adequate intake of carbohydrates, proteins, and lipids is essential for the activation of IS [7]. On the other hand, the malnutrition status is associated with IR commitment [7]. In addition to the macronutrients, micronutrients also have an important role in the IS. Even so, based on the dietary pattern, almost all subjects probably have a deficient intake of micronutrients, which may impair the performance of IS [7]. It is important to highlight that micronutrients act synergistically, in other words, the human body needs an adequate concentration of all micronutrients involved with the IR to guarantee the immune barrier of cells [8]. Other substances present in healthy nutrition, as some bioactive compounds, especially polyphenols, also play an important role in the IS, because of their antioxidant and anti-inflammatory properties [8]. They act by regulating immune cells, gene expression, and inhibiting certain pro-inflammatory cytokines [9]. Thus, both micronutrients and bioactive compounds might contribute to the adjuvant treatment of patients that have already infected with the SARS-CoV-2, since it targets specific IS cells, such as macrophage, NK cell and T cells [2] that could have responses potentiated by certain nutrients and bioactive compounds. This non-pharmacological intervention could help to decrease the severity of symptoms by modulating the host's IS.

It is important to note that, to the present moment, there is no solid information in the scientific literature showing how adequate nutrition status or specific food consumption could help to decrease SARS-CoV-2 spreads and control the COVID-19 current pandemic scenario progression. However, there are relevant evidences recent published showing the role of some micronutrients reducing risk of COVID-19 and other viral infections (e.g., Influenza), such as vitamin D [10-13], vitamin A, selenium, zinc [14, 15], copper [16] and vitamin C [17, 18].

A systematic review about potential interventions for COVID-19 suggests the importance of individually evaluation of nutritional status before administration of any treatment proposed [19], highlighting the synergic role of nutrients in IR. Besides, avoid nutritional deficiencies using effective and safe nutrition strategies may help to decrease the number of infected people [20].

Therefore, this review has as main objective to inform how micronutrients and bioactive compounds could act in the essential immunological pathways could stop SARS-CoV-2, focusing on the functions that have already established in the literature and transposing to this scenario.

Search strategy

Search strategy included PubMed using main keywords related to immunological responses, COVID-19, micronutrients and bioactive compounds (e.g., immune system, SARS-CoV-2, vitamins, minerals, polyphenols). Books and a food composition table complemented information about food sources, quantity and bioavailability of micronutrients and bioactive compounds. This review included COVID-19’s evidences published in the years 2019 and 2020. Also included micronutrients, bioactive compounds and immune responses articles published from the 1990s to 2020. In vivo (rodents and human experimental models) and in vitro studies were eligible when published in English or Portuguese. No systematic assessment and statistical analysis were performed.

Immunological responses and Covid-19

After the virus host invasion, the first recognition is made through the innate IS through pattern recognition receptors (PRRs), such as the retinoic acid-inducible gene I-like receptors [rig-I-like receptor (RLR)], which is responsible for recognizing viral genetic material [2, 21]. The inflammation cascade begins through the binding of SARS-CoV-2 to macrophages that consequently presents its antigens for TCD4 cells, generating their activation and also differentiation into T helper type 17 (Th17) cells, for example. Then, cytokines are produced to mobilize the entire adaptive IR. They are interleukins (IL) 1, 6, 8 and 21, tumor necrosis factor β (TNF-β), and monocyte chemoattractant protein-1 (MCP-1). These mediators stimulate T cells to activate natural killer cells (NK) and TCD8 cells [2]. TCD4 cells are responsible for producing specific antibodies to SARS-CoV-2 through the activation of B cells. TCD8 cells are important to viral control, since they are cytotoxic, playing a crucial role in the elimination of SARS-CoV-2 of the infected cells, and are associated with an immunological induction [2, 22].

To reach the cell's cytoplasm, the SARS-CoV-2 binds to a specific receptor, called dipeptidyl peptidase-4 (DPP4), through its spike glycoprotein (S), promoting adhesion between protein and receptor. To the viral genome presentation occurs, protein S needs to bind to the tool-like receptor (TLR)-4. The recognition of protein S triggers pro-inflammatory cytokines production through a primary response protein-dependent signaling pathway to myeloid differentiation factor-88 (MyD88). Then, it is observed the nuclear factor kappa B (NF-kB) activation, IL-1 and IL-6 production, in addition to type 1 interferon (IFN-1) and TNF-β [2].

Another pathway might be stimulated by binding viral RNA to the TLR-3 receptor, which induces the activation of inflammatory pathways through the interferon regulatory factors (IRF). Consequently, it culminates in IFN-1, IL-1, IL- 6, and TNF-β production as well. If the viral RNA binds to TLR-7 and/or TLR-9, it is also observed NF-kB and IRF activation. The presence of these cytokines attracts lymphocytes and leukocytes to the infected cell until the infection can be controlled [2]. It is important to highlight the role of IFN-1 in viral spread control. IFN-1 activate dendritic cells and NK, besides accelerate phagocytosis by macrophages of viral antigens [2, 21]. Figure 2 illustrates the process of immune activation.

Fig. 2

Immune response to SARS-CoV-2. The scheme shows the main cells and cytokines involved in the immune defense mechanism against COVID-19 described in this review. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; NK cell natural killer cell; Th 17 T helper type 17; IL-1 Interleukin 1; IL-6 Interleukin 6; IL-8 Interleukin 8, IL-21 Interleukin 21, TNF-β tumor necrosis factor β, MCP-1 monocyte chemoattractant protein-1, DPP4 dipeptidyl peptidase-4; S protein spike glycoprotein; TLR-3 tool-like receptor—3; TLR-4 tool-like receptor—4; TLR-7 tool-like receptor—7; TLR-9 tool-like receptor—9; MyD88 myeloid differentiation factor-88; NF-kB nuclear factor kappa B; IRF interferon regulatory factors. Red lines refer to inhibitory effects. Green lines refer to activating effects.

Adapted from Li et al. and Yi et al. [2, 10]

If there is an impairment of the immune barrier and the virus spread cannot be contained, SARS-CoV-2 proliferates and affects, principally, tissues that have a high expression of the angiotensin-converting enzyme 2 (ACE 2), like kidneys, intestine, lungs, brain, and cardiovascular system [23, 24]. The virus affinity to ACE 2 may be an explanation for patients who died of multiple organ failure [23]. Recently, Cheng H and colleagues [25] showed that the virus is dependent on the ACE 2 expression in the respiratory epithelium to be able to penetrate and start its replication. Then, the damaged cells generate the inflammatory cascade described above, starting with the presentation of the virus to lymphocytes and ending with pro-inflammatory cytokines liberation. The pro-inflammatory macrophages and granulocytes-mediated IR culminates in respiratory disorders, the main symptom in the most severe stage of the COVID-19 [24, 26]. Pro-inflammatory cytokines such as IL-1, IL-6, and TNF are found in high concentrations in the infected patient's lungs and could be a possible trigger for the formation of pulmonary mucus and fibroblasts induction [23]. Thus, strategies that allow to block or to reduce those pro-inflammatory cytokines' actions can benefit patients in more advanced stages of COVID-19 [24].

Micronutrients

Once the scientific knowledge about the mechanisms and processes involved in cells and cytokines activation and production related to the SARS-CoV-2 immune responses was previously presented, it is important to understand how some micronutrients could be fundamental for the IS homeostasis during SARS-CoV-2 infection. Some micronutrients are related to inhibiting, stimulating, or acting as a cofactor to cells and cytokine altered by that virus. Therefore, this section brings together the main vitamins and minerals that contribute to IS function.

Vitamin A

Some previous scientific reviews highlighted the importance of vitamin A to the proper function of innate IS cells, as NK cells and macrophages [8, 27]. Besides that, vitamin A is fundamental for both T and B cell performance and the mechanism of antibody production in response to the specific antigen [28, 29].

In vivo evidences

Its deficiency is associated with the reduced number and functionality of NK cells and increases of INF γ, and intervenes negatively in phagocytic and macrophages activities as well in experimental study with rodents [30].Also, deficient levels of vitamin A could affect the differentiation and quantity of T cells, reducing the generation of antibodies and consequently decreasing the response to the virus in rodents [31, 32].

In vitro evidences

Deficient status of vitamin A negatively affects the differentiation in growth of B cells [33].

Vitamin B6

Similar to vitamin A, vitamin B6 participates in the production of antibodies and NK cell activity [27, 28, 34]. It is necessary for cytokines and endogenous amino acids the synthesis and metabolism [29].

Vitamin B6 also assists in inflammation regulation, maintaining Th 1 responses and the process of lymphocyte proliferation, differentiation, and maturation in experimental studies in rodents [35, 36]. Besides, higher levels of B6 active form decreases inflammation in humans [37]. Its deficiency can lead to lymphocytopenia and consequent immune deficiency, decreasing antibody-mediated responses as well [38].

Vitamin B7

Biotin (vitamin B7 or vitamin H) is an essential co-factor for five carboxylases, known as biotin-dependent carboxylases, involved in metabolism of several pathways such as gluconeogenesis, branched-chain amino acids metabolism and fatty acid synthesis [39, 40]. Metabolic disorders can lead to changes in IS responses and inflammatory process caused by biotin deficiency [39].

Previous research shows that biotin deficiency can affect immune responses, enhancing T CD4 lymphocytes in humans’ blood samples [41]. Consequently, leading to an increased level of IFN-γ, TNF and IL-17 and enhance of proinflammatory responses [41]. Besides, dendritic cells leads to Th1 and Th17 responses through increased production of proinflammatory cytokines when biotin levels are insufficient [42].

Vitamin B9

Vitamin B9 or folate is involved in the NK cells cytotoxicity maintenance and the production and metabolism of antibodies, enabling a sufficient antigen response to the antigen [26, 27, 29].

Animal and humans studies show folate deficiency association with depressive immune response, impairing, for example, the proliferation of T cells [38]. In rodent model antibody responses can be improper in this situation [29].

Vitamin B12

As vitamin B12 is a cofactor in folate metabolism, it indirectly contributes to the production and metabolism of antibodies [28, 29, 34].

An important immunomodulator, vitamin B12 is associated with cytotoxic cells, as NK and TCD8, facilitating its production and helping to regulate the proportion between helper and cytotoxic T cells in humans [43, 44].

Vitamin C

Vitamin C is widely known for its antioxidant and immunomodulatory properties, capable to protect lymphocytes from oxidative stress [29]. It is fundamental to other antioxidant compounds regeneration, as glutathione and vitamin E, enabling conversion to their active form [45].

Vitamin C deficiency is related to increases in cell oxidative damage and in the incidence and severity of pneumonia cases in humans [46, 47].

Vitamin C is also involved in maintaining and improving the activity of NK cells and their chemotaxis [27, 28, 48, 49], removal, and macrophages-mediated neutrophils apoptosis in rodents and humans [50]. Besides, it can stimulate the production, function, and movement of leukocytes to the infection site [29, 47].

Lastly, vitamin C plays a role in T cells production, differentiation, and proliferation of T cells, resulting in cytotoxic T cell production and in the increase in the antibodies generation [29, 48, 50].

Vitamin D

Vitamin D is one of the most widely studied micronutrient involved with the IS function. Vitamin D receptors can be found in innate IS cells such as macrophages, monocytes, and dendritic cells [29].

This vitamin is able to increase the differentiation of monocytes to macrophages [48] and in its active form (i.e. calcitriol), it is associated to promote the macrophages movement and phagocytic capacity, improving their oxidative potential [28, 51–53]. Furthermore, vitamin D stimulates the proliferation of the immune cells, increases the synthesis of superoxide, and helps to protect against infection caused by pathogens [29].

About the adaptive IS, vitamin D can induce suppression in the B cells antibodies production and T cell proliferation [29].

In addition, vitamin D is related to inhibit T cytotoxic and helper cell functions and to promote T regulatory T cell production [49, 54, 55]. It can reduce the expression of pro-inflammatory cytokines and increase anti-inflammatory cytokines in vitro and in vivo experimental models [29, 51, 56–60].

Its deficiency increases the susceptibility and severity to infections, especially acute respiratory tract infections, decreases the number of lymphocytes, and increases morbidity and mortality in children [46, 61].

Vitamin E

Besides the anti-inflammatory profile, vitamin E is an important antioxidant compound, protecting cells against free radicals [29, 48].

Among its anti-inflammatory functions, vitamin E improves NK cell activity, lymphocyte proliferation, and T cell-mediated functions, helping to build immune synapses between T helper cells. Indirectly, vitamin E protects T cell functions by decreasing the production of prostaglandin E2 (PGE2) by macrophages, which has immunosuppressive activity in several studies in animal models and humans [27, 28, 48, 49, 62, 63]. Its deficiency can impair adaptive immunity, affecting the functions of T and B cells [29].

Copper

Copper is a mineral that accumulates at the site of inflammation [29, 34]. As the zinc, copper is directly related to the enzyme superoxide dismutase (SOD), important in the defense against reactive oxygen species (ROS) [28]. Thus, it is considered a free radical scavenger, capable of maintaining an intracellular antioxidant balance [28, 64].

To react against the infectious agents, copper acts on macrophages, accumulating in their phagolysosomes and improves the NK activity in rats [65, 66].

In addition, it participates in the differentiation and proliferation of T cells, the production of antibodies, and cellular immunity in animal studies [34, 35]. Its deficiency can cause an abnormal decrease in neutrophils and increase the susceptibility to infections in humans [29, 67, 68].

Iron

Iron is involved in the production and action of inflammatory cytokines such as IFN-γ, TNF-α, IL-2, and IL-10 [48], and it is also important to generate ROS that kills the pathogen that infects IS [29].

In relation to the adaptive IS, iron is involved in the differentiation and proliferation of T cells and assists to regulate the proportion between T helper and cytotoxic T cells [29, 49].

An adequate plasmatic iron level is able to modulate the IS, reducing the M1 macrophage's pro-inflammatory response in mice [69, 70]. Its deficiency can reduce the immune response in humans [38, 70]

Magnesium

In humans, magnesium is associated with DNA protection against oxidative damage [71].

In high concentrations, magnesium reduces superoxide anion production [72]. It fundamental to bind the antigens to macrophage RNA, to regulate leukocyte activation, it is a cofactor for antibodies synthesis and is involved in the regulation of apoptosis [65, 66].

Selenium

This mineral is essential for the selenoproteins activity, which is important for the host's antioxidant defense [19].

Selenoproteins may affect the NK cells and leukocytes functions and potentially reduce the exaggerated ROS production during the oxidative stress [27, 29, 34, 48, 73].

Selenium also participates in T cell differentiation and proliferation, improves T helper cell counts and antibody levels [34, 64, 74]. Its deficiency can impair cellular and humoral immunity, besides increasing the virulence during viral infections in humans and rats studies [29, 46, 74, 75].

Zinc

Zinc is an important antioxidant agent against both ROS and reactive nitrogen species (RNS) [45, 47].

Zinc is essential for the intracellular tyrosine kinase binds to T cells receptors, promoting the T lymphocytes development and activation [45, 47]. Besides that, zinc induces the T cytotoxic cells proliferation and is involved in the development of regulatory T cells (Treg) [49, 76–78].

This mineral is also an anti-inflammatory agent, able to modulate cytokines release through the regulation of development of pro-inflammatory cells, such as Th17 and Th19, and of the production of cytokines, such as IL-2, IL-6, and TNF-α in several studies with humans and animals, besides in vitro evidences [49, 76–81]. It contributes to the maintenance and improvement of the cytotoxic activity of NK cells, in the monocytes phagocytic capacity, it helps in the TCD8 cells proliferation, and it influences the activity of antioxidant proteins [27–29, 47–49, 78, 82, 83].

Zinc is also involved in the antibodies production, mainly immunoglobulin G (IgG), and in its response in animal models [28, 78, 84, 85].

Finally, adequate levels of zinc are important to maintain the host's immunological defense [49]. Its deficiency is associated with impairment of total IS, affecting the number and function of lymphocytes, particularly T cells, and leads to altered production of cytokines that contribute to oxidative stress and inflammation [29]. It may be associated with an increase in viral (particularly pneumonia) and respiratory infections in humans [38, 46].

In order for all micronutrients to perform their functions, attention must be paid to its intake according to the recommended daily dietary intake (RDA) for healthy individuals, which considers the age range of each individual. Table 1 provides this information for adults, besides to compile the main functions in the IS and food sources of each micronutrient. It is worth mentioning that, the daily values of these micronutrients might be changed, with the necessity for greater amounts of these compounds to provide ideal immune support [8].

Table 1

Micronutrients: food sources, immune system functions and recommendations

Micronutrient	Food sources [131]	Functions	Recommendation (RDA)—adults (18–70 years)	Quantity of micronutrients per 100 g of food [143, 144]
Copper	Liver, oysters, whole grains, oilseeds and chocolate	Intracellular antioxidant [64] Contributes to the inflammatory response [34] Acts on cell differentiation and proliferation [34] Assists in the NK cells activity [145] Involved in the antibodies Productions of antibodies and cellular immunity [28]	900 µg/day for both men and women	Brazilian nut—1.7 mg Chocolate 2.2 mg Cooked bovine liver—9.9 mg Cooked oysters—2 mg Hazelnut—1.5 mg Oat bran—0.4 mg
Iron	Meat, liver, legumes, seafood, dark green vegetables	Contributes to free radicals formation to react against viruses and bacteria [146] Participates in the T lymphocyte proliferation and differentiation [146] Participates in the enzymatic action against pathogens [147]	8 mg/day for men and 18 mg/day for women	Cooked beef—2.6 mg Cooked black beans—1.67 mg Cooked bovine liver—6.3 mg Cooked broccoli—0.8 mg Cooked chicken leg—2.1 mg Cooked green peas—1.63 mg Cooked pork—1.2 mg Cooked spinach—1.5 mg Steamed seafood—22 mg
Magnesium	Cereals and seeds, green leafy vegetables, seafood and oilseeds	Magnesium supplementation is correlated to improve lung function [148]	420 mg/day for men and 320 mg/day for women	Almonds—305.1 mg Cooked green beans—151 mg Cooked oysters—39 mg Cooked shrimp—34 mg Cooked spinach—68.4 mg Hazelnut—282.3 mg Pumpkin seed—532 mg Sesame—340.4 mg Sunflower seed—121 mg Wheat germ—321.4 mg
Selênium	Oilseeds, seafood and cereals	Essential for several enzymes involved in the redox balance [149] Increases T cells proliferation [149] Increases the Natural Killer cells activity [149] Improves the antiviral vaccine responses (including influenza vaccine) [149] Improves antiviral immunity [149] Decreases virulence of some influenza strains and other viruses [150]	55 µg/day for both men and women	Brazilian nut—126 µg Brown rice—2.7 µg Canned sardine in oil—46 µg Tuna—52.5 µg Whole wheat flour—13.6 µg
Vitamin A	Liver, fish liver oil, egg yolk, butter, green leafy vegetables, yellow-orange vegetables and fruits	Action in resistance to infections [151] Maintenance of the lymphocyte pool and T lymphocyte synthesis [151] Maintenance of epithelial cell differentiation and immune competence [151] Improves neutrophils, macrophages and Natural Killer cells functions [151] Role in the T lymphocytes differentiation [151] Role of prevention and treatment of respiratory tract infections [152]	900 µg/day for men and e 700 µg/day for women	Broccoli—279 µg Butter—1013 µg Carrot—1326 µg Cod liver oil—30,000 µg Cooked bovine liver—14,574 µg Egg yolk—148 µg kale—496 µg Manga—787 µg Spinach—484 µg
Vitamin B12	Meat, liver, fish, eggs, milk and dairy products	Immunomodulator [28] Acts on the NK cells functions [34] Assists in the T lymphocytes productions [34] Contributes indirectly to the antibodies' production and its metabolism [34]	2.4 µg/day for both men and women	Boiled egg—1 µg Cooked beef—2.5 µg Cooked bovine liver—112 µg Cooked chicken—0.36 µg Cooked salmon—2.8 µg Cooked trout—5 µg Cooked tuna—1.8 µg Cottage cheese—2.81 µg Steamed seafood—99 µg Whole milk—0.33 µg
Vitamin B6	Meat, bananas, broccoli, carrots, spinach and oilseeds	Helps in the inflammatory process regulation [34] Participates in the amino acids, cytokines and antibodies synthesis [34, 145] acts on the lymphocytes proliferation, differentiation, and maturation [145] Assists in NK cells activity [34]	Men 18–50 years: 1.3 mg/day 51–70 years : 1.7 mg/day Women 18–50 years : 1.3 mg/day 50–70 years : 1.5 mg/day	Banana—0.6 mg Bovine liver—1.43 mg Brazilian nuts—0.26 mg Carrot—0.23 mg Cooked beef—0.40 mg Cooked chicken—0.63 mg Hazelnut—0.6 mg Nuts—0.56 mg Spinach—0.15 mg
Vitamin B7	Seeds, oilseeds, eggs, soy protein, salmon, carrots and sweet potatoes	Important function in NK cells activity [42] Contributes to the generation of T lymphocytes [42] Important in the maturation and responsiveness of immune cells [42]	30 µg/day for both men and women	Boiled egg – 16.5 µg Carrot – 5 µg Cooked salmon – 5 µg Hazelnut – 75 µg Peanut – 101.4 µg Sweet potato—4.3 µg Wheat bran – 44.4 µg
Vitamin B9	Meat, bananas, broccoli, carrots, spinach and oilseeds	Contributes to the innate immunity maintenance [48] Contributes to the antibody response to antigen [34] Contributes to the T cells proliferation [34]	400 µg/day for both men and women	Boiled egg—40 µg Chicken liver—770 µg Cooked beans—149 µg Cooked bovine liver—220 µg Cooked white rice—60.7 µg Lentil—180 µg Pea—65 µg Spinach—108 µg Wheat germ—357 µg
Vitamin C	Citrus fruits, acerola, pineapple, strawberry, melon, tomato, pepper, broccoli and cabbage	Positive modulation of the aging process and immunosenescence [153] Positive modulation of the low-grade inflammatory process [153] Improves phagocyte motility and chemotaxis [50] Improves antibody levels, differentiation, and proliferation [50] Modulates positively production of inflammatory cytokines [50] Role in the prevention and treatment of respiratory infections [50] Decreases the pathogenicity of viruses, bacteria, parasites and fungi [154]	90 mg/day for men and 75 mg/day for women	Acerola—941.4 mg Broccoli—34.3 mg Cashew—219.3 mg Green Bell pepper—100.2 mg Kale—96.7 mg lemon—38.2 mg orange—53.7 mg Papaya—82.2 mg Passion fruit—19.8 mg Pineapple—34.6 mg Strawberry—63.6 mg Tomato—21.2 mg Yellow Bell pepper—201.4 mg
Vitamin D	Fish liver oil, milk and dairy Products, butter, eggs, fat cheeses	Stimulates the innate immune response in bronchial epithelial cells [155] Stimulates the monocytes to macrophages differentiation [155] Stimulates antibacterial protein synthesis [155] Stimulates the mechanisms associated with the pathogens elimination [155] Supplementation seems to have a protective effect in respiratory tract diseases (mainly in individuals with hypovitaminosis D) [156] Individuals with hypovitaminosis are more susceptible to respiratory tract infections [157]	15 µg/day for both men and women	Boiled egg—13 µg Butter—1.54 µg Cheddar cheese—0.32 µg Cod liver oil—252 µg Fortified milk—1 µg
Vitamin E	Vegetable oils, wheat germ, egg, dark green vegetables, nuts and almonds	Membrane antioxidant—cell protection [158] Stimulates lymphocyte proliferation [158] Supplementation associated with antibacterial effects [158] Increases the activity of NK cells [158] It seems to have a protective effect against pneumonia and colds [137]	15 mg/ day for both men and women	Almond –5.5 mg Broccoli—1.05 mg Cabbage—0.61 mg Canola oil—21.3 mg Corn oil—21.3 mg Egg—1 mg Nuts –2.6 mg Peanut—7 mg Spinach—0.95 mg Sunflower oil—51.5 mg Wheat germ—19.1 mg
Zinc	Meat, seafood, oilseeds, whole grains and fortified grains	Function in the immune cells maturation and differentiation [159] Zinc deficiency is related to impaired innate immunity [159] Increases the Natural Killer cells activity and number [159] Regulation of inflammatory cytokines [160]) Participation in anti-inflammatory pathways [160]	11 mg/day for men and 8 mg/day for women	Boiled flank—8 mg Cashew nuts—4.7 mg Cooked brown rice—0.7 mg Cooked oyster—39 mg Grilled fillet—5.1 mg Popcorn—2 mg Roasted Tiger fish 2.1 mg Rolled oats—2.6 mg Wholemeal bread—1.6 mg

In addition, it is common an inadequate daily intake of vitamins and minerals, even when the accessibility to food is easy. For that case, supplementation may be necessary to improve specifics immune responses [8]. However, when this supplementation is in very high doses, it can cause unfavorable consequences for metabolism (e.g., hypervitaminosis) and IS, highlighting a bigger risk for vitamin A, iron and copper [29, 34]. To exemplify, in a small study with humans, high intake of copper for a long period was capable to reduce antibody production to an influenza vaccine [86].

If supplementation is necessary, it is important to respect safety limits previous established by Institute of Medicine (IOM) [8, 87]. Besides, it is essential to consult high quality studies previous published with consistent experimental design [8].

Bioactive compounds

Bioactive compounds are essential and nonessential compounds, widely found in fruits and vegetables [88]. They are responsible for colors, flavors, and they are related to potential pharmacological activities on human health [88, 89]. This compounds have many classifications, such as polyphenols, phytosterols, terpenoids, organosulfur compounds and alkaloids [90]. Many polyphenols have an important impact on IS through the immune cells modulation, the cytokines production, and pro-inflammatory genes expression [91, 92]. This section will present the main immune cells and pathways that are positively related to bioactive compounds.

Inflammation and oxidative stress

Some polyphenols are known for their anti-inflammatory potentials. According to in vivo and in human cells studies, resveratrol can inhibit pro-inflammatory cytokines, such as TNF-α and IL-6, while curcumin contributes to reducing TNF and IL-1. Curcumin also induces a reduction in NF-kB activation and in the TLR 2 and 4 expression [93-99]. In experimental designs using human cells, Epigallocatechin gallate (EGCG) and gingerol, present in green tea and ginger respectively, are other polyphenols that contribute to the NF-kb function [95, 100–102].

Polyphenols intake is directly associated with IS cell count and differentiation. Some studies in vitro, rodents and in humans experimental models observed alterations in the NK cells, macrophages, dendritic cells, Th1, and TCD4 cells count [91, 103–105]. Other types of T helper can be modulated, such as Th9 and Th17, by EGCG as well [106].

Several in vivo and in vitro studies show polyphenols’ anti-inflammatories properties that induce free radicals elimination, metal ions chelation, NADPH oxidase inhibition. The polyphenols contribute to the mitochondrial respiratory chain, they also induce a reduction in exaggerated ROS production, by inhibiting some enzymes involved and positively regulating antioxidant enzymes [9].

Regarding metals, curcumin can play a role in chelating transition metals, as Cu2+ and Fe2+, while quercetin and ECGC chelate Fe2+ in cell culture using THP1-monocytes [107]. Resveratrol and curcumin are the polyphenols that can inhibit NADPH oxidase in culture cells studies [108-110]. Curcumin, EGCG, phenolic acids, capsaicin, quercetin, anthocyanins, and resveratrol inhibit xanthine oxidase, an enzyme related to the ROS formation in mice and in vitro experiments [111-116]. Besides that, in vivo evidences, curcumin can stimulate the production of SOD, catalase, and glutathione peroxidase, antioxidant enzymes that are associated with decreases in ROS formation [117]. EGCG improves the activity of SOD and glutathione peroxidase, in vivo [118].

Cytokines modulation

Inflammatory cytokines modulation is one of the most studied mechanisms of polyphenols immunomodulation [9]. Their properties on macrophages were observed in an animal-model study with Chinese propolis administration in rodent “RAW 264.7” macrophages. The polyphenols present in Chinese propolis induced cyclooxygenase 2 (COX 2) and inducible nitric oxide synthase (iNOS) inhibition and a consequent reduction in the TNF-α, IL-1 β and IL-6 expression [119]. Similarly, this phenomenon was also observed when chamomile extract and quercetin alone were administrated [120]. Besides that, a clinical study highlighted that extra virgin olive oil has been related to reduce IL-6 and C-reactive protein (CRP) expression [121]. Quercetin and catechins have an effect on the balance of pro and anti-inflammatory cytokine production in vitro studies, increasing the IL-10 release and inhibiting TNF-α and IL-1 β [122, 123].

NF-kB signaling pathways

Polyphenols can modulate NF-kB at various points during the activation cascade, which induces an important anti-inflammatory effect through an alteration in the binding of the NF-kB complex to DNA, as an example [9]. In addition, in a previous study was observed a similar phenomenon when quercetin was administered in rodent BV-2 microglia cells [124]. Galangin, a flavonoid present in propolis, can control the NF-kB translocation and consequently decrease TNF-α, IL-6, IL-1β, and IL-8 expression [125]. At least in studies that were developed in cell culture, other polyphenols involved with NF-kB signaling pathways are resveratrol, catechins, and epicatechins [126, 127].

Besides that, it is important to highlight the role of EGCG on Wistar rat's respiratory epithelial cells NF-kb inhibition [128, 129], once it could improve the scientific knowledge between bioactive compounds properties and COVID-19 pandemic control.

Especially in virus infection, it is important to highlight a finding in human culture cell study and curcumin intervention [130]. This polyphenol provided an antiviral effect against enveloped viruses, inhibiting Zika and Chikungunya virus replication. This can be explained because curcumin may interferes with virus-cell binding, reducing its infectivity [130].

It is worth mentioning that only a healthy, varied, and fruits and vegetables-based diet is able to ensure exposure to all of these bioactive compounds [89]. In this way, an adequate supply of both bioactive compounds and micronutrients is guaranteed, as well as the synergy between vitamins and minerals [7, 8]. Table 2 provides a summary of the main functions of some bioactive compounds and the food sources in which they are found. To a better comprehension of all the mechanisms cited in this article, Fig. 3 shows which point of the SARS-CoV-2 infection pathway the main immunomodulatory polyphenols and micronutrients may act on.

Table 2

Foods, bioactive compounds, their effects and other considerations

Food	Bioactive compounds	Effects	Considerations
Açai Berry (Euterpe oleracea)	Flavonoids (pp. anthocyanins)	Antioxidant Anti-inflammatory	Increased antioxidant enzyme activity, vasodilator, and antidiabetic effect. Açai berry plays a role in the prevention and in the treatment of comorbidities that may aggravate COVID-19 symptoms [161, 162]
Citric Fruits	Polyphenols/vitamin C	Antioxidant Immunomodulator	Vitamin C improves chemotaxis, improves neutrophil phagocytic capacity and oxidative death, and supports lymphocyte proliferation and function. Polyphenols have an important antioxidant and anti-inflammatory function [50, 163]
Cocoa (Theobroma cacao)	Flavonoids (pp. Catechins)	Antioxidant Anti-inflammatory Antiviral	Cell protection against free radicals and unscheduled apoptosis. Evidence shows cocoa's protective action against some influenza strains [164, 165]
Garlic (Allium sativum L.)	Allicin and thiosulfinates	Antibiotic Antifungal Antivirals Anti-inflammatory	Protective action against the flu virus (in addition to other viruses such as cytomegalovirus and herpes) [166–168]
Ginger (Zingiber officinale Roscoe)	Gingerols	Antioxidant Anti-inflammatory	In addition to the anti-inflammatory property, there is evidence that indicates an improvement in respiratory function, shorter duration of mechanical ventilation and shorter intensive care unit hospitalization in patients with Acute Respiratory Distress Syndrome [169, 170]
Grapes and grapes-derived products	Resveratrol	Antioxidant Anti-inflammatory	In addition to the already known properties of resveratrol in chronic non-communicable diseases, evidence shows immunomodulatory functions and infectious disease prevention. The protective effect in vitro studies with coronavirus (less cell death, less cytotoxicity and greater cell viability after treatment with resveratrol). At higher doses, Resveratrol contributes to reducing viral replication [171, 172]
Kefir	Probiotics	Antimicrobial Immunomodulator Anti-inflammatory	Kefir is associated with a healthy microbiota (as a pathogen barrier). Some benefits, such as increased macrophage activity and cytokine production, are related to immunomodulatory effects [173, 174]
Linseed (Linum usitatissimum L.) and Linseed oil	Polyunsaturated fatty acids (Ω-3)	Anti-inflammatory Immunomodulator	Due to its fatty acid content, linseed has an anti-inflammatory effect (the increase of anti-inflammatory properties substances and the decrease in inflammatory cytokines) [175–177]
Propolis	Phenolic compounds (pp. flavonoids)	Antimicrobial Antiviral Antifungal Antioxidant Anti-inflammatory	Although there is no sufficient clinical studies, experimental and in vitro studies show propolis as a potentially protective factor against various infections and is related to the healing process [178–180]
Turmeric (Curcuma longa)	Curcuminoid pigments (Curcumin)	Antivirals Anti-inflammatory Antioxidant	Anti-inflammatory and antioxidant properties, as well as action against various viruses, bacteria, and fungi. Besides that, a study correlates curcumin analogs as a treatment of influenza [130, 181, 182]

Fig. 3

Immune response to SARS-CoV-2 and micronutrients and polyphenols participation in the various cells and cytokines involved in the defense mechanisms. Polyphenols 1 resveratrol, curcumin, EGCG, gingerol, epicatechins, catechins, quercetin, propolis, Polyphenols 2 resveratrol, curcumin, EGCG, quercetin, anthocyanins; Polyphenols 3 resveratrol, curcumin, catechin, quercetin, olive oil, chamomile extract, propolis; Polyphenol 4 curcumin; Polyphenol 5 EGCG; Polyphenol 6 propolis. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; NK cell natural killer cell; Th 17 T helper type 17; IL-1 Interleukin 1; IL-6 Interleukin 6, IL-8 Interleukin 8; IL-21 Interleukin 21; TNF-β tumor necrosis factor β; MCP-1 monocyte chemoattractant protein-1, DPP4 dipeptidyl peptidase-4; S protein spike glycoprotein; TLR-3 tool-like receptor—3; TLR-4 tool-like receptor—4; TLR-7 tool-like receptor—7; TLR-9 tool-like receptor—s9; MyD88 myeloid differentiation factor-88; NF-kB nuclear factor kappa B; IRF interferon regulatory factors; ROS reactive oxygen species. Red lines refer to inhibitory effects. Green lines refer to activating effects

Immune system and elderly

Aging is a natural and complex process associated with uncountable human body physiological alterations, such as reductions in bone and muscle mass, in the basal metabolism rate (BMR), and total body water. Aging is also related to teeth loos, which can cause damage to the chewing, saliva production decrease, and dysphagia [131]. In this population, these changes also affect the immune system, a process characterized by immunosenescence, which can be defined as a reduced ability to respond to "foreign" antigens and to tolerate self-antigens. Thus, immunosenescence would be associated with a greater susceptibility to infections (including COVID-19), to cancer, to vaccination failure, and to autoimmune diseases [132].

Immunosenescence induces both the innate and adaptive IS modification and is associated with persistent low-grade inflammation. As the men have a more severe age-related immune function alteration than women, they suffer more from its effects [133]. Age-related decrease in phagocytosis, antigens presentation, in immune cells cytotoxic potential, lymphocyte number and function, are observed in this population. Besides that, these changes make the elderly more susceptible to infections, affect the ability to respond to pathogens and cause an exacerbation of the symptoms of these infections [134].

Decreased function of the thymus (an important lymphocyte maturation organ) and the loss of function and differentiation capacity of hematopoietic stem cells are some of them are some hypotheses that attempt to explain the aging-related immune function decline. It is also known that lifestyle during adulthood can directly influence this process: food, nutritional status, physical activity, social isolation, smoking, exposure to alcohol and drugs are factors that affect the degree of decline in the IS in the elderly [27]. The maintenance of an adequate nutritional status, a satisfactory supply of macro and micronutrients, ingestion of bioactive compounds, and the regular practice of physical activity can positively modulate the immune response of these individuals. Besides that, nutritional status can be highlighted as a vital condition for a healthy IS operation. Studies report that elderly people with protein-calorie malnutrition have a lower IR compared to those with adequate nutritional status [134].

In addition to protein-calorie malnutrition, commonly observed in aging, attention should be paid to the micronutrient supply of this a group. Although energy requirements to the elderly are lower, the micronutrients (vitamins and minerals) recommendation remains almost unchanged. Frequently, old people ingest less food than what was recommended, it can induce micronutrients deficiency and consequent impairment of IS and IR. Adequate dietary guidance and possible supplementation could be tools to prevent and/or reverse deficiencies of these nutrients [27].

Vitamin D deficiency, which is quite prevalent in the general population and especially in the elderly, induces impaired immune responses to influenza vaccination [135]. The literature also shows that vitamin D supplementation is associated with improving the immune response of patients with this vitamin deficiency [136]. Konijeti et al. [136] and Hemilä [137] demonstrated that vitamin E supplementation may be able to reduce the incidence of pneumonia in adult and elderly men [137]. Bouamama et al. [138] indicated that vitamins C and E supplementation improved the T lymphocytes response in the elderly and could contribute to the prevention of age-related immune system impairment.

In addition to a higher infection incidence, the elderly are more susceptible to prolonged infections, exacerbated symptoms, and complications. More than half of the elderly with a common cold develop a respiratory disease (e.g. pneumonia) and they have more than tenfold chances of death when compared to young adults. Since the beginning of the COVID-19 pandemic, advanced age has been highlighted as a risk factor for both susceptibilities to symptoms and to the infection outcome. In this way, death a common finding in individuals over 70 years and are associated with age-related physiological changes in IS [27, 139].

In Italy, approximately 87% of the first 2,000 cases of deaths were over 70 years old [140]. Another study compared the mortality rate between American elderly residents [mean 83 (range 51–100) years] and healthy workers and visitors [mean: 43 (range 21–79) years] of a long-term care institution that were positively diagnosed with SARS-CoV-2. The researchers found that 34% of elderly residents and 0% of workers die due to Covid-19. These results show that the disease affects the elderly more severely [140, 141]. Thus, special attention should be given to elderly individuals and to how to improve their immune system, especially those with other risk factors. In this scenario, adequate dietary planning that provides nutritional support within the current recommendations could contribute to a more competent IR, which can result in better chances of SARS-CoV-2 prevention and treatment. During more severe infection episodes, the elderly may have an increased requirement for these nutrients and it might be necessary to evaluate their supplementation.

Final considerations

The literature shows that some infected individuals have their sense of smell and taste affected [142] it is in turn associated with food intake reduction and lack of appetite. Based on that, the elaboration of the specific guidelines is interesting to help with a better understanding between nutrition and current COVID-19 pandemic treatment. For example, it is important to know which foods are better tolerated, respecting the individual's preference. Another example is to stimulate the consumption of harvest fruits and vegetables, once their flavor is more prominent. Besides that, other important nutritional strategies are to add natural spices in the preparation, to do memory exercise regarding the preparation that will be ingested and improving its acceptance, and to make the patient aware of the importance of their food for the correct IS function and the consequent response to COVID-19 [142].

Based on all information present in this review, in conclusion, a healthy, varied, and vegetables and fruits-based diet is important to ensure the IS balance and the consequent IR to SARS-CoV-2. It is worth mentioning the essential role of a qualified nutrition scientist to prescribe individualized guidance that considers a previous disease historic, nutritional status, and age as well.