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
figure 1

Adapted from Li et al. [2]

Structural scheme of the SARS-CoV-2.

Full size image

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 [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].

In vivo evidences

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].

In vitro evidences

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].

In vitro evidences

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, 51,52,53]. 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 vivo evidences

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, 56,57,58,59,60].

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].

In vivo evidences

Among its anti-inflammatory functions, vitamin E improves NK cell activity, lymphocyte proliferation, and T cell-mediated functions, hel** 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].

In vivo evidences

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 vitro evidences

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].

In vivo evidences

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 vivo evidences

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

In vitro evidences

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].

In vivo evidences

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].

In vitro evidences

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, 76,77,78].

In vivo evidences

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, 76,77,78,79,80,81]. 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 [27,28,29, 47,48,49, 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
Full size table

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 [93,94,95,96,97,98,99]. 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, 100,101,102].

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, 103,104,105]. 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 [108,109,110]. 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 [111,112,113,114,115,116]. 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
Full size table
Fig. 3
figure 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

Full size image

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.