Biological Trace Element Research (2023) 201:1596–1614

https://doi.org/10.1007/s12011-022-03290-8

Immunomodulatory Role of Microelements in COVID‑19 Outcome:

a Relationship with Nutritional Status
Roldán‑Bretón Nuria Renata1 · González‑Rascón Anna Arely2 · Leija‑Montoya Ana Gabriela1 ·
Mejía‑León María Esther1

Received: 21 March 2022 / Accepted: 16 May 2022 / Published online: 6 June 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-
CoV-2 infection can activate innate and adaptive immune responses and result in massive inflammatory responses in the
disease. A comprehensive understanding of the participation of micronutrients in the immune response to COVID-19 will
allow the creation of prevention and supplementation scenarios in malnutrition states. Microelement deficiency can be deci-
sive in the progression of diseases and their optimal levels can act as protective factors, helping to maintain homeostasis.
Vitamin A, B, D, selenium, zinc, and copper, through their complementary and synergistic effects, allow the components of
innate and adaptive immunity to counteract infections like those occurring in the respiratory tract.
Thus, alterations in nutritional status are related to metabolic diseases, systemic inflammation, and deterioration of the
immune system that alter the response against viral infections, such as COVID-19. The aim of this review is to describe the
micronutrients that play an important role as immunomodulators and its relationship between malnutrition and the develop-
ment of respiratory infections with an emphasis on severe and critical COVID-19. We conclude that although an unbalanced
diet is not the only risk factor that predisposes to COVID-19, a correct and balanced diet, which provides the optimal amount
of micronutrients and favors an adequate nutritional status, could confer beneficial effects for prevention and improvement
of clinical results. The potential usefulness of micronutrient supplementation in special cases is highlighted.

Keywords SARS-CoV-2 · COVID-19 · Nutritional status · Micronutrients · Immune system · Microelements

Introduction factor for respiratory virus infections that increase the bur-
den of disease [2]. An optimal nutritional status is achieved
SARS-CoV-2 has been spreading at high speed globally and through the consumption of a balanced and quality diet,
with it, the emergence of the COVID-19 pandemic since which would provide all of the needed micronutrients in the
December 2019. As of May 6, 2022, the World Health appropriate quantity to guarantee an optimal response and
Organization (WHO) reported 513,955,910 confirmed cases thus prevent infections. Many studies suggest that nutrients
of COVID-19 and more than 6.2 million deaths worldwide are involved in the development of COVID-19 [2–5]; how-
[1]. The lack of pharmacological treatments against COVID- ever, only a few of them directly assess nutrient deficiencies
19 urges us to highlight the importance of micronutrient-rich in patients with the disease, and fewer clinical assays study
diets with a preventive approach. Immune system dysfunc- the influence of micronutrients in viral immune response.
tion due a poor diet and nutrient deficiency is a major risk There are several kinds of malnutrition: undernutri-
tion, inadequate vitamins or minerals, overweight, obesity,
and resulting diet-related non-communicable diseases [6].
* Mejía‑León María Esther
[email protected] Although the prevalence of malnutrition has decreased in
recent decades, WHO [1] reported that 1.9 billion adults
1
Facultad de Medicina Mexicali, Universidad Autónoma de are overweight or obese, while 462 million are underweight.
Baja California, Dr. Humberto Torres Sanginés S/N, Centro Obesity has increased uncontrollably and it coexists with
Cívico, 21000 Mexicali, Baja California, México
underweight even in the same region of the world. The con-
2
Facultad de Odontología Mexicali, Universidad Autónoma de cept of the obesity-related double burden of malnutrition has
Baja California, Mexicali, Baja California, México

13
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1597

emerged with important clinical implications. When obesity the biogenesis of viral replication organelles establish a pro-
occurs, micronutrient deficiencies and clinical manifesta- tective microenvironment that favors viral genomic RNA
tions of malnutrition are possible and complicate its clinical replication and transcription. Structural proteins translocate
course. This effect is due to a combination of a sedentary into endoplasmic reticulum, where newly produced genomic
lifestyle, an inadequate diet, and alterations inherent in the RNA binds into lumen of secretory vesicular compartments,
pathophysiology of obesity. Among its consequences are the which ends in secretion of virios by exocytosis [11].
inability to maintain body composition and function, loss Structural nucleocapsid protein (NP) protects the viral
of skeletal muscle, and a negative impact on both morbidity RNA genome and packages it into a ribonucleoprotein
and mortality [7]. complex [12]. Moreover, N protein has been identified in
The effect of micronutrients on immune system func- mechanisms to antagonize the host human response involv-
tion and their role as regulators of oxidative stress helps ing interaction and suppression of cellular antiviral-RNAi
to understand the greater vulnerability of the patient with [13]. The membrane (M) protein encircles the capsid and
obesity to SARS-CoV-2 infection. For example, diets rich in anchors the envelope (E) and S proteins. E protein par-
vitamin A, B, D, zinc, selenium, and copper promote a bet- ticipates in virus budding by regulation of viral lysis, viral
ter response of the immune system against viral infections, genome release, and activation of host inflammasome [8,
including severe acute respiratory syndrome coronavirus 2 14]. So far, many SARS-CoV-2 mutant strains or variants
(SARS-CoV-2) [4]. have been reported and mutations located at RBD-ACE2 are
In this review, we aim to describe and summarize the role associated with loss efficacy of vaccines and neutralizing
of micronutrients in the immune response against SARS- antibodies [15, 16]. These strains are classified as variants
CoV-2 and the development of COVID-19 disease. We of concern (VOCs) [17], as the N501Y mutation present in
hypothesize that there is a strong correlation between malnu- variants from the UK (Alfa), South Africa (Beta), and Brazil
trition and the development of severe and critical illnesses. (Gamma) that has shown an increase in ACE2 affinity caus-
If we consider that micronutrients fulfill various biological ing enhanced infectivity and more severe COVID-19 [8, 18].
functions and that their deficiency has a negative influence
on nutritional status, it is possible to explain the increased
vulnerability of individuals to viral infection and to identify
key diet components as a possible preventive and therapeutic Pathophysiology and Stages of COVID‑19
strategy against COVID-19. Disease

COVID-19 may manifest with symptoms such as fever, dry

SARS‑CoV‑2 cough, fatigue, shortness of breath, muscle pain, confusion,
headache, sore throat, rhinorrhea, chest pain, diarrhea, nau-
SARS-CoV2 is an enveloped virus of 80–120 nm size and sea, vomiting, chills, sputum production, hemoptysis, dysp-
member of the betacoronavirus family, responsible for the nea, bilateral pneumonia, anorexia, chest pain, leukopenia,
coronavirus disease 2019 (COVID-19). Its viral genome lymphopenia, olfactory and taste disorders, and higher levels
consists of a single-stranded RNA-positive of up to 32 kb of plasma cytokines, such as IL-2, IL-7, IL-10, GSCF, IP10,
length that encodes 4 structural proteins, 16 nonstructural MCP1, MIP1A, and TNFα in critically ill patients [19].
proteins (NSPs), and nine accessory proteins [8]. The spike COVID-19 disease is classified into three levels based on the
(S) protein is essential for binding to the host; it is a glyco- severity of the disease: mild, severe, and critical, where most
sylated homotrimer that can be cleaved by furin-like pro- patients only present mild symptoms and recover [20]. The
tease in S1 and S2 functional subunits. S1 protein recog- main symptoms of the mild disease are fever, cough, fatigue,
nizes, through a receptor-binding domain (RBD), the human ground-glass opacities in chest CT imaging, and mild pneu-
angiotensin-converting enzyme 2 (ACE2) as its main recep- monia, while in severe disease, other symptoms may also
tor [8]. ACE2 is expressed in the host cellular membrane in appear, such as dyspnea, blood oxygen saturation ≤ 93%,
many cell types, including alveolar, endothelial, and renal respiratory rate ≥ 30/min, arterial oxygen partial pressure
cells [9]. S2 harbors the fusion peptide (FP) which anchors to inspired oxygen fraction ratio < 300, and/or pulmonary
to target membranes and mediates membrane fusion by con- infiltrates > 50% in 24 to 48 h. Finally, at a critical stage,
necting with lipid bilayers of the host cell, while S1 plays a acute respiratory distress syndrome (ARDS), respiratory
key role in bringing viral and cellular membranes into close failure, septic shock and/or multiple organ dysfunction or
proximity to permit lipid bilayer fusion [10]. Following viral failure, difficult to correct metabolic acidosis, septic shock,
uptake and further release of RNA, translation of ORF1 and and coagulation dysfunction may occur [19]. Nevertheless,
ORF2 results in pp1a and pp1b, which form the viral repli- a large number of cases with asymptomatic infection not
cation and transcription complex. Expression of NSPS and requiring hospitalization were also reported [21].

13
1598 R.-B. N. Renata et al.

Lung Immune Function and Response As a consequence of immune defense and cell signal-
Against SARS‑CoV‑2 ing mechanisms after infection, excessively generated ROS
causes oxidative stress, a condition of imbalance between
The immune response developed in the presence of a viral free radical generation and antioxidant defenses. Free radi-
infection activates innate and adaptive mechanisms. As cals generated in excess are hydroxyl radical (OH-), super-
part of the innate response, the skin and all mucous mem- oxide anion radical (O2–), hydrogen peroxide (H2O2), and
branes that form physical and chemical barriers integrate the peroxyl (ROO-). These are toxic to the cell because they
first line of defense against the virus. Upon infection with are capable of reacting with biomolecules such as DNA,
SARS-CoV-2 and when the virus has successfully overcome RNA, proteins, carbohydrates, and lipids, damaging cells
the first line of defense, virus antigens that are known as and tissues and initiating inflammatory processes [27]. In
pathogen-associated molecular patterns (PAMPs) activate addition, neutrophils are among the main producers of ROS
the synthesis of antimicrobial substances in serum, such and are found to be elevated in critically ill patients. The
as interferons (IFN) and complement proteins. Respiratory mechanisms by which oxidative stress intervenes in viral
tract epithelial cells are equipped with pathogen recognition virulence are still under study. Some authors hypothesize
receptors (PRRs) that recognize viral antigens and respond that it may be a consequence of immune response modula-
by producing inflammatory mediators such as IL-1β, TNFα, tion or due to an increase in the mutation rate as a result of
and type 1 IFNs. These cytokines enhance recruitment of oxidative damage [28].
circulating cells as neutrophils, macrophages, and NK cells, The antioxidant systems that evolved to alleviate ROS-
which in turn cause phagocytosis and cytokine secretion associated damage in mammals are regulated by the expres-
and, as an antiviral response, can promote cell death. When sion of nuclear factor erythroid 2p45-related factor 2 (Nrf2).
innate-cell barriers are surpassed and infection of epithelial Under normal conditions, Nrf2 is retained in the cytoplasm
cells occur, their interaction with myeloid cells contributes by a group of proteins and rapidly degrades unless activated.
to activation of adaptive antiviral responses [22, 23]. However, during oxidative stress, Nrf2 is activated and stim-
Myeloid cells act as detectors of viral infections and are ulates a variety of genes responsible for cytoprotection and
a key component of the antiviral response, including the detoxification. It was found that some viruses can suppress
coordination of immune responses and tissue homeostasis the Nrf2 pathway, thus affecting the antioxidant response
repair mechanisms. Dendritic cells (DCs), monocytes, and in the body. In particular, respiratory viral infections were
macrophages modulate the immune response by releasing shown to be associated with inhibition of Nrf2 and activa-
a variety of proinflammatory cytokines, such as IL-1β, tion of the nuclear factor-kappa B (NF-κB) pathway, leading
IL-6, IL-8, and TNFα, which influence the cellular and to increased oxidative damage and promoting inflammation
humoral response toward coronavirus infection and relate [29, 30]. Higher levels of lung inflammation caused by this
to its severity [24]. Patients with severe COVID-19 show abnormal proinflammatory immune response led to ARDS
increased numbers of mature and immature neutrophils and worse outcomes and differential gene expression profiles
and monocytes in the blood and a significant reduction identified NF-κB signaling as a potential regulator in disease
in circulating lymphocytes as well as dendritic cells [23]. severity [28]. The production of ROS is mediated by the
DCs are present in lung tissue; therefore, they recognize activity of the nicotinamide adenine dinucleotide phosphate
antigens from infected-tract respiratory epithelial cells and (NADPH) oxidase (NOX) family, which consists of seven
initiate adaptive immune responses by presenting antigens members: NOX1 to NOX5 and two dual oxidases, Duox1
to naïve T lymphocytes, generating CD4 + and CD8 + T lym- and Duox2, expressed in most cell types. NOX4 isoform
phocytes. While CD4 + T cell subsets participate, produc- upregulates after viral infection in lung epithelial cells and
ing an array of cytokines to coordinate immune responses, is responsible for ROS generation, which activates protein
CD8 + T cells cause apoptosis of infected cells and secrete kinases that favor viral ribonucleoprotein nuclear export and
cytokines to promote NK activation. Alveolar macrophages promote viral replication [31]. Interestingly, NOX4-derived
are able to phagocyte large numbers of microorganisms, but ROS production has been shown to modulate the binding of
also produce reactive oxygen species (ROS) and can migrate SARS-CoV-2 to ACE2. Therefore, in COVID-19, the imbal-
to nearby lymph tissue carrying antigen for presentation ance in the cellular redox state with an excess of free radicals
[25]. B lymphocytes produce a variety of antibodies that (ROS) and activation of inflammatory signaling pathways
function as opsonins to facilitate phagocytosis and promote cause tissue damage [27].
complement activation and antibody-dependent cellular In older adults, Abouhashem et al. [32] found that some
cytotoxicity by NK cells. Patients with severe COVID-19 redox-active genes are downregulated in lung cells, when
presented antibody titer to S protein, which was previously analyzing single-cell RNA sequencing data from healthy
mentioned as fundamental for viral uptake [26]. donors, compared to samples from young donors. Among

13
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1599

them, the superoxide dismutase 3 (SOD3) gene stands out, as well as the expression of Th1- and Th17-associated
followed by activating transcription factor 4 (ATF4) and cytokines. The duration of immune memory for SARS-
metallothionein 2A (M2TA). These findings suggest a weak- CoV-2 infection is still under investigation to provide
ening of the cellular antioxidant systems in the lung associ- certainty on the defense mechanisms.
ated with aging, which could partly explain the severity in
this age group.
Another group of proteins that mediate the antiviral Impact of Nutritional Status on Immune
response, which is especially important in the context of Response and Severity of COVID‑19 Disease
coronavirus infection, are IFN, a group of signaling mol-
ecules that play an important role in the impaired control of Recently, it has been proposed that nutrition is partly respon-
viral replication. This is due to an inadequate pre-existing sible for the wide differences in COVID-19 mortality rates
immunity and the delayed or inadequate type I interferon-I observed between countries and even within regions of
(IFN-I) responses that likely contribute to the pathogenesis the same country [37], as is shown in Fig. 1. Nutrition can
of severe COVID-19. IFN-I antagonism is a central mecha- certainly affect the ability of the immune system to pro-
nism of virulence for many viruses, and SARS-CoV-2 is no tect against viral infections. Malnutrition in the elderly in
different in this regard [24]. COVID-19 has been described in a Chinese study. This
Antiviral memory response involves the action of T and study of 182 elderly patients (age ≥ 65 years) with COVID-
B lymphocytes. When the infection subsides, 10% of these 19 showed that 52.7% were “malnourished” and a further
cells persist overtime to protect the organism against rein- 27.5% were “at risk of malnutrition,” when using the Mini
fection. In COVID-19, T cells and virus-specific T cells Nutritional Assessment score. The regression risk in the
are essential to protect against viral infection; however, the study also showed diabetes mellitus to be an independ-
memory immune response is still being studied to under- ent risk factor for malnutrition (OR: 2.12; IC del 95%:
stand SARS-CoV-2 infection. Lymphopenia is a typical pro- 1.92–3.21; p = 0.006) [38].
file in patients with COVID-19 and could be a key element Optimal immune function depends on an adequate
related to disease severity and mortality, especially in elderly nutrition that ensures a good supply of nutrients (macro
sick patients in whom marked CD8 + T cell lymphopenia and micronutrients) for healthy immune response devel-
and increased neutrophils are reported; on the other hand, opment and support. In this sense, different studies have
patients who overcome the disease gradually recovered associated low levels of micronutrients with the develop-
their basal T cell levels [33]. A clinical trial has reported ment of severe or critical disease [5, 39–42]. The main
an increase of immunoglobulin G (IgG) antibody titers in nutrients implicated in viral protection, by their antioxi-
patients with follow-up after 2 weeks of hospital discharge dant capacity or by being part of immune function, are
[34]. This study also found that most patients showed serum vitamins A, C, D, E, B6, B12, folic acid, iron, zinc, cop-
neutralizing activity in a pseudotype entry assay. Notably, per, selenium, and magnesium. Antioxidant capacity and
there was a strong correlation between neutralizing antibody antioxidant response potential of the host are two of the
titers and the number of virus-specific T cells. Moreover, a key determinants of the outcome of SARS-CoV-2 infec-
nucleocapsid protein (NP)-specific antibody response has tion. Hence, the higher antioxidant capacity of children
been reported [35]. However, virus-specific T cells and their and young adults combined with their higher expression
relationship to neutralizing antibody titers in patients with of ACE2 is the likely explanation for the low incidence of
COVID-19 remain uncharacterized. severe infections in these age groups. This hypothesis also
In a recent study of individuals recovered from mild explains the occasional severe infections in the younger
symptomatic COVID-19, at 3 months post-infection, the age groups because, regardless of age, anyone with a
formation of virus-specific immune memory cells with reduced antioxidant defense system would be expected
the protective function was detected. Recovered indi- to have a more severe infection. Also, an inadequate die-
viduals had increased neutralizing antibodies, classical tary intake of antioxidants, high intake of prooxidants,
pathogen-specific memory B cells IgG + with BCRs or excessive alcohol consumption, which decreases total
that formed neutralizing antibodies, Th1 cytokine- antioxidant capacity, could be additional hidden risk fac-
producing CXCR5 + circulating Tfh and CXCR5- non- tors in addition to age and comorbid conditions [28].
Tfh cells, proliferating CXCR3 + CD4 + memory cells, In elderly patients, there are more cases of malnutrition
and IFN-γ-producing CD8 + T cells [36]. Regarding and comorbidities such as diabetes mellitus and cardiovascu-
CD4 + memory T cells, in patients in the study by lar disease, and a weakened immune system, causing an inef-
Rodda et al. [36], they showed the ability to proliferate ficient response to the virus. Micronutrient deficiency leads
after re-exposure to peak protein by rapidly increas- to an impaired immune response, with inadequate cytokine
ing ICOS and CD40L levels in CXCR5 + and CXCR5, secretion, alterations in secretory antibody response, and

13
1600 R.-B. N. Renata et al.

Fig. 1  Micronutrient regulation of individual response in SARS- imbalance allows the SARS-CoV-2 virus to develop and causes the
CoV-2 infection. An optimal state of health can be achieved when different clinical forms of the disease (asymptomatic, mild, moderate,
the necessary quality and quantity of micronutrients such as Vit A, and severe). Vit A deficiency leads to the first defense barrier lack-
B, and D, as well as Se, Zn, and Cu, are provided through the diet. ing important components of innate immunity, which enhances the
This brings benefits that are reflected in an adequate nutritional state virus response. Vit B and Se play a role in the immune and antioxi-
that will provide the necessary elements that allow the immune sys- dant response against oxidative stress during infection. Vit B, D, Se,
tem to respond to an infection. Serious health problems such as obe- Zn, and Cu participate in a very important way, promoting the inhibi-
sity, metabolic syndrome, diabetes, and immunosuppression are a tion of the synthesis of pro-inflammatory cytokines that trigger the
result of the imbalance in the intake of foods with high caloric con- cytokine storm and therefore modulate the adaptive immune response
tent and low amount of micronutrients. Currently, with the ongoing by suppressing the Th1 response and promoting the production of
COVID-19 pandemic, it has become clear that the most vulnerable cytokines by Th2 cells. Zn, for its part, is involved in the transduc-
individuals to develop the infection are those in whom the balance of tion of signals in the cell and, therefore, in the patterns of cellular and
the physiological-nutritional status and immune system is lost. This viral gene expression, thus avoiding viral mutagenesis

antibody affinity, resulting in an increased susceptibility to Obesity represents an inflammatory state associated with
viral infection. It is widely recognized that in conditions of chronic activation of the immune system due to accumu-
obesity and overweight, there is a micronutrient deficiency, lated fat and the endocrine role of the adipocyte produc-
and the reason is that diets rich in ultra-processed foods, ing adipocytokines. Inflammation associated with obesity
high in fat and carbohydrates, not only promote weight has been related to an altered lung function and decreased
gain but are also often poor in vitamins and minerals [43]. defense mechanisms and immune system response, which
Nutritional transition has led the population to consume consequently enhance infection rates and probability of vac-
food with a low nutritional value affecting their health, but cination failure. Excess fat has also been correlated with
if nutritional information is available, people could improve an overactivation of the complement system that leads to
their diet quality. As household income decreases, diets are the development of the “cytokine storm,” as well as with
likely to shift towards cheaper, more energy-dense and less overexpression of ACE2, produced by mature adipocytes
micronutrient-dense foods. Promotion of an adequate and [45]. If the effect of the obesity-related double burden of
balanced diet could allow the consumer to experience food malnutrition is added to this clinical picture, it is possible
safety that favors better health and directly impacts the to understand more clearly the susceptibility of the obese
response of the immune system to infections [44]. patient to COVID-19.

13
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1601

Role of Micronutrients During the Viral further inflammation. In these cases, the number and activ-
Infection of SARS‑CoV‑2 ity of lymphoid cells decrease, such as natural killer cells,
which can lead to an inefficient antiviral response [47].
Vitamin A Alterations in the epithelium and lung parenchyma have
been described in infants with low levels of Vit A, a condi-
Vitamin A (Vit A) and carotenoids, derived from plants, tion that is associated with an increased risk of respiratory
have three bioactive forms: retinoic acid (RA), retinal, and diseases and pulmonary dysfunction [49]. It also has been
retinol that carry out very important biological functions reported that children with subclinical Vit A deficiency
like maintenance of vision, growth, and integrity of epi- are more likely to have recurrent respiratory infections
thelial and mucosal tissue that lines every external surface [50]. Critically ill COVID-19 patients have reduced lev-
exposed to microorganisms. Thus, Vit A plays a role in the els of Tregs and interferon-gamma, so this balance is lost
first line of defense against pathogen invasion by promot- when SARS-CoV-2 infection occurs [51]. Thus, Vit A
ing mucin secretion and participating as a promoter of cell contributes to the maintenance of homeostasis between
morphology and differentiation, especially, in the respira- anti-inflammatory and proinflammatory stimuli.
tory and gut epithelium. In a study conducted by Tomasa-Irriguible et al. [5] in
Vit A deficiency reduces the innate immune response Badalona, Spain, 120 hospitalized COVID-19 patients,
affecting the mechanical barrier function of epithelia and with ARDS criteria, were analyzed and 50 of these patients
enhances respiratory and intestinal infections [46]. Mucin were admitted to the intensive care unit (ICU). Of them,
production in these epithelia is regulated by retinoic 71.7% had low Vit A levels in plasma, with a mean value
acid; hence, moderate-dose vitamin A supplementation of 0.17 mg/L (normal levels > 0.3 mg/L). Low Vit A levels
improves barrier integrity by regulating gene expression were associated with male sex (69% vs. 45%, p = 0.02), with
of epithelial growth factors and related cytokines [47]. the need for ICU admission (62.1% vs. 20.7%; p = 0.048),
RA exerts its effects on skin and mucous membranes orotracheal intubation (OTI) rate (92.3% vs. 7.7%;
through direct mechanisms that regulate gene expression p = 0.0001), with the need for prone decubitus (93.6% vs.
by activating the nuclear retinoic acid receptor (RAR), 6.4%; p = 0.0001), the need for noradrenaline (92.9% vs.
which forms a heterodimer with the retinoid X receptor 7.1%; p = 0.001), and a higher rate of bacterial respiratory
(RXR). Once in the cell nucleus, this complex binds to superinfection (95.7% vs. 4.3%; p = 0.017). All deceased
specific retinoic acid response elements (RARE), which patients from this study had low vitamin A levels, but a sta-
dissociate the repressors and favors the transcription of tistical association between Vit A deficiency and mortality
target genes [48]. was not found.
RXRs and RARs are also expressed in immune cells In contrast, in a multicenter, observational, cross-sec-
such as B and T lymphocytes, and in dendritic cells tional, prospective analysis investigation conducted in Ger-
(DCs), the most important antigen-presenting cells that many, the researchers detected a strong association between
activate virgin T helper cells and lead to T cell differentia- Vit A deficiency and the development of ARDS and mor-
tion according to the presented antigen. Vit A metabolite tality (OR 5.21 [1.06–25.5], p = 0.042). Forty hospitalized
RA has a central role in the proliferation and differentia- patients with SARS-CoV-2 infection and diagnosed with
tion of innate and adaptive immune cells. At normal RA moderate, severe, and critical ARDS were included in the
levels, the differentiation of immune cells leads to a bal- study. The control group consisted of 47 recovered patients
anced population of anti-inflammatory regulatory T cells with only mild symptoms who did not require hospitaliza-
(Treg) and proinflammatory effector T cells, which can tion, and the results of the study revealed that Vit A defi-
produce interferon-gamma. RA regulates the differentia- ciency was higher as ARDS severity increased and signifi-
tion of dendritic cells, which present antigens to CD4 + T cantly lower in the recovered group (p < 0.01 to p < 0.001).
cells that induce Th17 inflammatory responses and secrete In this study, a Vit A concentration > 2 mg/L was considered
IL-17. On the other hand, in non-inflammatory states, RA low [51] (see Table 1).
promotes Treg cells by the reduction of IL-6 secretion A theory presented by Sarohan [52] links defective
that negatively regulates the Th17 response and prevents metabolism of retinoic acid with COVID-19. Accordingly,
an excessive immune reaction [48]. A balance between the RIG-I pathway decreases, and the immune defense
Helper T cells and Regulatory T cells is necessary for the mechanism shifts to the activated TLR3, TLR7, TLR8,
appropriate development of immune responses. TLR9, MDA5, and UPS pathways found in neutrophil,
Vit A deficiency alters the phagocytic and bactericidal macrophage, and dendritic cells. This causes a cytokine
activity of other cells of the innate immune system such storm through the activation of NF-κB pathway, resulting
as neutrophils and macrophages; this situation leads to in severe clinical presentations. In this situation, stored Vit

13
 Table 1  Summary of clinical studies findings regarding respiratory viral infections and COVID-19 in association with microelement concentrations
1602

Authors, year Country Participants/study type Outcomes

13
Vitamin A Zhang et al. 2020 [50] China 277,064 children Subclinical Vit A deficiency (serum Vit A < 0.2 mg/L) prevalence of
0–14 years old 10.4%
Cross-sectional study Children with recurrent respiratory infections were more vulnerable to
subclinical Vit A deficiency (21.3%, 95% CI: 20.5–22.2%)
Tepasse et al. 2021 [51] Germany 40 COVID-19 hospitalized patients: Gradual association between low Vit A levels and greater severity of
-Moderate (n = 9): 54 (30–81) years old COVID-19. Patients with serum Vit A < 0.2 mg/L were significantly
-Severe (n = 9): 50 (39–73) years old associated with the development of acute respiratory distress syn-
-Critical (n = 22): 58 (41–82) years old drome (OR = 5.54 [1.01–30.26]; p = 0.048), mortality (OR 5.21 CI
47 age-matched convalescent persons (control group): 54 (41–70) 1.06–25.5, p = 0.042), and inflammatory markers, such as c-reactive
years old protein, ferritin, albumin, and lymphocyte count (p < 0.001)
Prospective, multicenter observational cross-sectional study
Tomasa—Irriguible et al. 2021 [5] Spain 120 hospitalized COVID-19 patients, with acute respiratory distress Low levels of Vit A in 71.7% of patients, with a mean value of
syndrome criteria 0.17 ± 0.06 mg/L (normal levels > 0.3 mg/L). Vit A deficiency was
Cross-sectional descriptive study associated with male sex (69% vs. 45%, p = 0.02), with the need for
ICU admission (62.1% vs. 20.7%; p = 0.048), the orotracheal intuba-
tion rate (92.3% vs. 7.7%; p = 0.000), the need for prone position
(93.6% vs. 6.4%; p = 0.0001), the need for norepinephrine (92.9% vs.
7.1%; p = 0.001), and a higher rate of respiratory bacterial superin-
fection (92.6% vs. 7.4%; p = 0.016)
Al-Saleh et al. 2022 [53] Saudi Arabia 155 COVID-19 patients Low levels of Vit A in 36.5% of patients (normal levels > 0.34 µg/mL)
18–95 years old A 23% decrease in Vit A in patients with severe symptoms, which
-Asymptomatic (n = 16) disappeared after adjusting for inflammatory markers
-Mild (n = 49)
-Moderate (n = 68)
-Severe (n = 22)
Cross-sectional descriptive study
Vitamin B Itelman et al. 2020 [58] Israel 162 COVID-19 patients Folic acid levels were significantly lower in severe patients when
52 ± 20 years old compared with moderate and mild cases (9.6 ng/mL vs. 12.9 ng/mL
-Mild (n = 92) vs. 18.2 ng/mL, p = 0.005)
-Moderate (n = 44) A total of 80.8% of patients with severe COVID-19 were admitted to
-Severe (n = 26) the intensive care unit (p =  < 0.001). All deaths were in the severe
Cohort study disease subgroup (19.2%)
Deschasaux—Tanguy et al. 2021 [57] France 7766 adults SARS-CoV-2 negative participants had a higher intake of Vit B9 when
-311 positive for anti-SARS-CoV-2 antibodies compared with positive patients (330 ± 90 µg/day and 320 ± 90 µg/
NutriNet-Santé web-based cohort study day, respectively, p = 0.004). Dietary intake of Vit B9 (OR = 0.84 CI
0.72, 0.98, p = 0.02) was associated with a decreased probability of
SARS-CoV-2 infection
Tan et al. 2020 [59] Singapore 43 hospitalized COVID-19 patients Patients with Vit B12, D, and Mg supplementation had a lower need to
> 50 years old start oxygen therapy (OR 0.13, 95% CI 0.03–0.59) and intensive care
-Intervention group: Vitamin B12, D, and Mg supplementation support (OR 0.20 95% CI 0.04–0.93) than the control group, during
(n = 17) their hospital stay
-Control group (n = 23)
Cohort observational study
R.-B. N. Renata et al.
 Table 1  (continued)
Authors, year Country Participants/study type Outcomes

Vitamin D Rodriguez et al. 2020 [68] Mexico 172 COVID-19 patients Vit D deficiency in 68% of patients
51.44 ± 14 years old No significant differences were found between mortality and Vit D
Cross-sectional observational study levels (deceased 13.6 ± 6.36 ng/mL vs. survivors 17.30 ± 7.44 ng/
mL, p = 0.25). Patients with Vit D < 8 ng/mL have a 3.69-fold risk
of dying compared to those with levels > 8 ng/mL (OR 3.69, CI
1.62–8.37, p = 0.001)

Kaufman et al. 2020 [66] USA 191,779 patients who underwent SARS-CoV-2 testing, who had Vit Patients with deficiency (< 20 ng/mL) of Vit D (n = 39,190) had a
D testing results from the previous 12 months higher positivity rate for SARS-CoV-2 than those with adequate
Retrospective, observational study (30–34 ng/mL) Vit D levels (12.5%, CI, 12.2–12.8% vs. 8.1%, CI
7.8–8.4%)
SARS-CoV-2 positivity was strongly and inversely associated with cir-
culating Vit D (R2 = 0.96), a relationship that persists across latitudes,
races/ethnicities, both sexes, and age ranges

Hastie et al. 2021 [67] UK 341,484 UK Biobank participants Vit D serum concentration was associated with severe COVID-19
-203 died due to COVID-19 infection and mortality (HR 0.92; 95% CI 0.86–0.98; p = 0.016), but
Retrospective, observational study not after adjustment for confounders (HR 0.98; 95% CI 0.91–1.06;
p = 0.696)

Al-Saleh et al. 2022 [53] Saudi Arabia 155 COVID-19 patients Low levels of Vit D3 in 68% of patients (normal levels > 20.05 µg/mL)
18–95 years old Twelve of sixteen deceased patients had Vit D3 levels < 12 µg/mL
-Asymptomatic (n = 16) (mean 5.09 µg/mL), but without differences with Vit D3 levels in
-Mild (n = 49) survivors (4.81 µg/mL)
-Moderate (n = 68) No association between vit D3 levels and severity, total antioxidant
-Severe (n = 22) capacity, or superoxide dismutase was detected, after adjusting for
Cross-sectional observational study inflammatory markers and laboratory parameters
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional…
1603

13
 Table 1  (continued)
1604

Authors, year Country Participants/study type Outcomes

Selenium

13
Moghaddam, et al. 2020 [41] Germany 33 COVID-19 patients A total of 44.4% of COVID-19 patient samples were Se deficient
166 consecutive serum samples (normal levels 45.7–131.6 µg/L). Serum Se levels were significantly
Cross-sectional observational study lower in deceased COVID-19 patients vs. survivors (40.8 ± 8.1 µg/L
vs. 53.3 ± 16.2, p < 0.001)
A total of 39.6% of COVID-19 patient samples were deficient in
SELENOP (normal levels 2.56–6.63 mg/L)
Serum Se and SELENOP showed the expected strong correlation
(r = 0.7758, p < 0.001)
A total of 64.7% of deceased COVID-19 patients were Se deficient and
70.6% were SELENOP deficient while 39.3% and 32.6% of surviving
patients were Se and SELENOP deficient, respectively

Kocak, et al. 2021 [77] Turkey 92 adults Serum Se levels were significantly lower in SARS-CoV-2 infected
-SARS-CoV-2 infected (n = 60) patients when compared with healthy adults (255.23 ± 42.67 ppb vs
-Healthy (n = 32) 255.23 ± 42.67 ppb, respectively
Observational study Patients with mild, moderate, and severe disease had significantly
lower selenium levels than healthy, asymptomatic patients
(p < 0.001), suggesting that serum Se level is important in asympto-
matic treatment of the disease

Razeghi, et al. 2021 [3] Iran 84 COVID-19 patients Serum Se was as follows: 47.07 ± 20.82 ng/mL, 47.36 ± 25.6 ng/mL,
-Mild (n = 38) 29.86 ± 11.48 ng/mL in the mild, moderate, and severe disease group,
-Moderate (n = 27) respectively
-Severe (n = 19) Significant negative association between serum Se level and COVID-
Observational study 19 severity (standardized coefficient =  − 0.28, p = 0.01)

Al-Saleh, et al. 2022 [53] Saudi Arabia 155 COVID-19 patients Thirty percent of total participants were deficient in Se (< 70.08 µg/L)
18–95 years old Patients with severe symptoms were Se deficient in 18% of the cases
-Asymptomatic (n = 16) Se was independently associated with COVID-19 severity (p = 0.214)
-Mild (n = 49)
-Moderate (n = 68)
-Severe (n = 22)
Cross-sectional observational study
R.-B. N. Renata et al.
 Table 1  (continued)
Authors, year Country Participants/study type Outcomes

Zinc Jothimani, et al. 2020 [88] India 47 COVID-19 patients Low zinc levels in 57.4% of COVID-19 patients (normal reference
45 healthy controls levels: 71.8–79.6 µg/dl). COVID-19 patients had significantly lower
Prospective study Zn levels in comparison to the healthy controls: median 74.5 µg/dl
(IQR 53.4–94.6 µg/dl) versus 105.8 µg/dl (IQR 95.65–120.90 µg/dl),
p < 0.001)
COVID-19 patients with ZN deficiency had a higher risk for develop-
ing complications (OR 5.54, IC del 95%: 1.56–19.6, p = 0.008) and
for mortality (OR 5.48, 95% CI 0.61–49.35, p = 0.129)

Zeng, et al. 2021 [89] China 306 hospitalized COVID-19 patients Non-severe cases had higher Zn levels 6.61 (5.91–7.25) µg/L than
-Severe cases (n = 104, 34.0%) severe cases 6.18 (5.67–6.79) µg/L, p < 0.001
-Non‐severe cases (n = 202, 66.0%) Reference Zn normal levels: 4.3–7.8 mg/L
Retrospective cohort study A correlation between Zn and magnesium levels (CC 0.36 p < 0.05),
as well as Zn and iron (CC 0.64 p < 0.05), was detected, suggesting a
possible synergic effect in COVID-19

Kocak, et al. 2021 [77] Turkey 92 adults Zn serum levels in COVID-19 patients were lower
-SARS-CoV-2 infected (n = 60) (588.17 ± 195.02 ppb) than those of healthy participants
-Healthy (n = 32) (873.4 ± 335.38 ppb, p < 0.001)
Observational study A gradual decrease between Zn levels and severity were detected when
assigning COVID-19 patients into groups of mild, moderate, and
severe disease manifestations (p < 0.0001)

Al-Saleh, et al. 2022 [53] Saudi Arabia 155 COVID-19 patients Low levels of Zn in 25% of patients (Zn deficiency: < 0.693 µg/mL)
18–95 years old No association between Zn levels and severity, vitamin E, and vitamin
-Asymptomatic (n = 16) D3 serum levels was detected, after adjusting for inflammatory mark-
-Mild (n = 49) ers and laboratory parameters
-Moderate (n = 68)
-Severe (n = 22)
Cross-sectional observational study
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional…
1605

13
 Table 1  (continued)
1606

Authors, year Country Participants/study type Outcomes

Cooper

13
Hackler, et al. 2021 [103] Germany 35 hospitalized COVID-19 patients High levels of Cu were associated with survival (Cu;
173 consecutive serum samples 1475.9 ± 22.7 µg/L vs. 1317.9 ± 43.9 µg/L; p < 0.001), the same
way its biomarker, ceruloplasmin (CP; 547.2 ± 19.5 mg/L vs.
438.8 ± 32.9 mg/L, p = 0.086)
A positive linear correlation between Cu and Se levels was detected
in COVID-19 patients, but not consistent during the acute phase
response (R = 0.23, p = 0.003)

Zeng, et al. 2021 [89] China 306 hospitalized COVID-19 patients Higher Cu levels in severe COVID-19 patients (929.73, 828.52–
Severe cases (n = 104, 34.0%), non‐severe cases (n = 202, 66.0%) 1080.02 µg/L) than in non-severe cases (838.55, 770.47–
Retrospective cohort study 950.13 µg/L)
Cu reference normal levels: 634.1–999.4 µg/L

Kocak, et al. 2021 [77] Turkey 92 adults No significant difference between COVID-19 patients Cu
-SARS-CoV-2 infected (n = 60) serum levels (952.48 ± 388.75 ppb) and healthy participants
-Healthy (n = 32) (2795.99 ± 9605.09 ppb) was detected, p > 0.05
Observational study The Zn/Cu ratio in COVID-19 patients (median ± SD, 0.68 ± 0.28)
vs healthy patients (median ± SD, 0.86 ± 0.63) was not significant.
However, the Zn/Cu ratio showed a significant positive correlation
with hemoglobin

Al-Saleh, et al. 2022 [53] Saudi Arabia 155 COVID-19 patients Low levels of Cu in 3.2% of patients. Cu reference levels: 1 < 0.701 µg/
18–95 years old mL
-Asymptomatic (n = 16) Asymptomatic (1.30 ± 0.678 µg/mL), mild (1.31 ± 0.351 µg/mL), mod-
-Mild (n = 49) erate (1.25 ± 0.341 µg/mL), and severe (1.22 ± 0.370 µg/mL)
-Moderate (n = 68) Eighty-three percent of patients having a Cu/Zn ratio > 1. This ratio is
-Severe (n = 22) associated with COVID-19 severity when adjusted for inflammatory
Cross-sectional observational study marker parameters (p < 0.05)

Vit A, vitamin A; mg/L, milligrams per liter; CI, confidence interval; OR, odds ratio; COVID-19, coronavirus disease 2019; SARS-CoV-2, respiratory syndrome coronavirus 2; ICU, intensive
care unit; µg/mL, micrograms per milliliter; ng/mL, nanograms per milliliter; µg/day, micrograms per day; µg/L, micrograms per liter; Vit B9, vitamin B9; Vit B12, vitamin B12; Vit D, vitamina
D; Mg, magnesium; Vit B3, vitamin B3; HR, hazard ratio; SELENOP, selenoprotein P; ppb, parts per billion; Cu, cooper; Se, selenium; Zn, zinc; CP, ceruloplasmin
R.-B. N. Renata et al.
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1607

A is quickly depleted, because of an overuse of retinoic acid has also been associated with Vit B12 malabsorption trigger-
in the RIG-I pathway and the IFN-I synthesis pathway, a ing deficiency. Therefore, it could make these patients more
process that is called “Retinoic Acid Depletion Syndrome” susceptible to infections [4].
(RADS). Such theories highlight the importance of further Several studies have reported a possible association
research into Vit A and its relationship to the development between deficiency of Vit B compounds with COVID-19
and response towards viral infections. A more recent study (Table 1) [4, 38, 54, 56]. For example, in 311 French par-
of 155 older patients (18–95 years) showed 36.5% were Vit ticipants of the NutriNet-Santé study, a lower consumption
A deficient (< 0.343 mg/L); authors suggest that the patient of Vit B9 was detected in patients positive for SARS-CoV-2
with COVID-19 disease depletes serum Vit A storage. The when compared to 7455 healthy participants (OR = 0.84
immune response mechanism changes from innate to adap- (0.72,0.98), p = 0.02) [57]. In Israel, 162 patients diagnosed
tive, preventing retinoic acids from being used, showing that with severe COVID-19 showed lower folate levels than mod-
inflammation balances the relationship between COVID-19 erate and mild cases (9.6 ng/mL vs 12.9 ng/mL vs 18.2 ng/
severity and Vit A levels [53]. mL, respectively, p = 0.005) of which 12% were immunosup-
pressed, 9% required non-invasive oxygenation, and 15%
Vitamin B were intubated [58]. In another cohort of patients from Sin-
gapore, in which 43 COVID-19 patients over 50 years old
Thiamine (B1), riboflavin (B2), niacin (B3), pantothenic participated [59], it was detected that joint supplementation
acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), and of Vit B12, Vit D, and magnesium, when admitted to the
cobalamin (B12) are 8 compounds that form the water-solu- hospital, was associated with a decrease in severity of the
ble vitamin B (Vit B) complex that can be obtained through disease. In supplemented patients, there was an association
the diet, mainly from plants or red meat. Individual or as a with less need for oxygen therapy (17.6 vs 61.5%, p = 0.006)
complex, these vitamins can play an important role in the and a decrease in the need for intensive care, when compared
metabolism of proteins, lipids, and nucleic acids. They also to those who did not receive supplements of these micronu-
play a role in the immune response and in the antioxidant trients. Although these studies support the involvement of
response against oxidative stress [54]. B vitamins in COVID-19 severity, clinical trials are needed
Vit B12 is essential for DNA synthesis and regulation; to prove a causal association.
its deficiency alters DNA and RNA synthesis because of its
participation as a cofactor of methionine synthase. Transco- Vitamin D
balamins exert their antioxidant mechanism facilitating the
bioavailability of reduced glutathione in the cytosol and, Vitamin D (Vit D) levels depend on diet and exposure to
therefore, promote the synthesis of oxidized glutathione. UVB radiation, where 7-dehydrocholesterol 25 (OH) D is
Cobalamin is produced by the intestinal microbiota and obtained and then converted to its active form, calcitriol
contributes to the regulation of the gut-brain axis, protects 1,25 (OH) D, in the liver, kidneys, or other cells, including
against intestinal dysbiosis, and favors the production of alveolar macrophages, lung epithelial cells, dendritic cells,
microbial metabolites in adequate proportions, with a posi- and lymphocytes. Although, the main studied effect of this
tive impact at the metabolic level, contrary to what happens fat-soluble vitamin is involved in bone homeostasis through
in a deficient state [55]. These processes are vital for DNA the regulation of calcium and phosphorus metabolism, and
synthesis, cell homeostasis, hematopoiesis, and immunity. participates in immune function regulation. Vit D stimulates
Under physiological conditions, Vit B12 regulates the innate cellular immunity by inducing the production of anti-
expression of anti-inflammatory cytokines and growth fac- microbial peptides that are involved in antiviral responses
tors, which reduces systemic inflammation. In addition, by such as cathelicidins, IL-37, and defensins. Vit D inhibits the
promoting the increase of NK cells and CD8 + T cells, it cytokine storm by reducing the production of proinflamma-
improves the immune response and regulates the antivi- tory cytokines (IFNγ, IFNß, TNFα, and IL6) and enhancing
ral response. Its modulatory participation in the function regulatory cytokine IL-10, and it also modulates the function
of phagocytic cells, interferon production, maturation of T of immune cells by regulating adaptive immune response,
lymphocytes, and viral replication has been described. When suppressing the Th1 response and promoting the production
Vit B12 is deficient, there is a greater risk of infections and of Th2 cytokines[60]. It is possible that lung production of
an increase in their severity [55]. Some factors such as age the active form of Vit D is associated with the role of this
and the use of some drugs are associated with a higher risk microelement in the immune response towards respiratory
of Vit B12 deficiency. In elderly, the decrease in the produc- infections [23].
tion of intrinsic factor results in B12 malabsorption, poor Different mechanisms that conduct to the described
nutrition, or increased urinary and intestinal losses [38]. The effects of Vit D have been reported. For example, Vit D
administration of metformin as a treatment of type 2 diabetes can induce an increase in IKBa levels, NF-κB inhibitor, in

13
1608 R.-B. N. Renata et al.

pulmonary epithelial cells that are infected with the respira- UK Biobank participants (mortality per 10 nmol/L 25(OH)D
tory syncytial virus. The inhibition of this transcription fac- HR 0.98; 95% CI = 0.91–1.06; p = 0.696). The same is con-
tor decreases the expression of target genes such as IFN-β firmed by other research groups, one with a sample of 155
and CXCL10, regulating the inflammatory process [61]. Vit patients from Saudi Arabia [58], in which 103 participants
D also reduces the effect of TGF-β on the development of (68.2%) had low vitamin D3 values but without association
fibrosis, prevents apoptosis of alveolar epithelial cells, and when performed bivariate analyses. Another study in 172
participates in the maintenance of the pulmonary epithelium Mexican COVID-19 patients [68] detected an association
integrity by regulating the renin-angiotensin axis. Thus, as only in those patients with Vit D levels < 8 ng/mL with a
a whole, these mechanisms protect the pulmonary epithe- 3.69-fold risk of mortality, but without risk differences in
lium and favors the resolution of ARDS, as demonstrated patients with higher concentrations. Despite this, it is evi-
by Zheng et al. [62] in a murine model with LPS-induced dent that the relationship of Vit D deficiency derived from
lung injury. comorbidities such as obesity, diabetes, or natural non-mod-
Vit D is one of the most studied micronutrients in the ifiable factors such as age and ethnicity has a relationship
progression of COVID-19 as shown in Table 1. Since the that adds to the nutritional status of the patient, leaving this
beginning of the pandemic, its use as a supplement has been population vulnerable to virus infection.
suggested around the world, due to its potential preventive
effects. These theories arise from different studies that have Selenium
reported Vit D deficiency in patients with COVID-19, in
association with the severity of disease and with the admis- Selenium (Se) is an essential micronutrient of relevance as
sion to ICU, being a more pronounced deficiency in adults part of the proteinogenic amino acid selenocysteine (Sec),
older than 70 years [39, 63, 64]. In addition to age, eth- for which an elaborate biochemical pathway has been devel-
nicity is another factor that has been associated with Vit oped and conserved in many species [69]. The main activity
D deficiency and the possibility of being a risk factor for of Se in the organism is carried out due to its presence as a
COVID-19. Research by Hastie et al. [40] shows an asso- component in the structure of selenoproteins. Its functions
ciation of black and South Asian ethnicity with confirmed include maintenance of the REDOX balance in cells, its
COVID-19 (OR = 5.49, 95% CI = 3.82 to 7.88, p < 0.001; antioxidant and anti-inflammatory activity, and the regu-
OR = 2.76, 95% CI = 1.74 to 4.39, p < 0.001, respectively) lation of endoplasmic reticulum stress. A diet deficient in
when compared with white ethnicity. However, when adjust- Se may result in a loss of immunocompetence leading to
ing the model considering Vit D values, the ORs remained increased susceptibility to viral infections and cancer. Both
with minimal changes without modifying statistical signifi- its dietary restriction and the suppression in the expression
cance. Therefore, despite being related, their simultaneous of selenoproteins have been associated with higher levels of
presence does not potentiate the risk of COVID-19. pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, in a
Marcola et al. [65] evaluated the results of different stud- variety of tissues, including the gastrointestinal tract, uterus,
ies on Vit D, seeking to determine if the associations with mammary gland tissues, and lung tissue [70]. Therefore, Se
the reduction in the severity of COVID-19 are due to a pos- appears to play an important role in fighting viral diseases,
sible causal relationship. Their review gathers evidence that such as COVID-19 [27, 71].
meets Hill’s criteria for temporality, strength of association, To date, twenty-five genes encoding selenoproteins have
dose–response relationship, consistency of findings, plausi- been identified [71], such as selenoprotein F, K, M, N, and
bility, accounting for alternate explanations, and consistency S that fold proteins and protect against oxidative stress from
with known facts. However, there is a lack of clinical trials the endoplasmic reticulum [72]. There is also the SELENOP
to experimentally confirm these associations, which makes antioxidant defense role, which, as it is the most abundant,
associations inconclusive [39, 63, 64]. For example, in an is used as a biomarker of Se status [73]. Glutathione peroxi-
observational study in the USA with 191,779 patients [66], dase 1 (GPX1) is one of the selenoproteins most affected by
a higher percentage of positivity for SARS-CoV-2 was found Se deficiency [74]. Considering that virus infection increases
in those with Vit D levels below 20 ng/mL (12.5%, 95% oxidative stress, GPX1 comprises a key defense against ROS
CI, 12.2–12.8%) when compared with patients with levels by its enzymatic function catalyzing the detoxification of
above 55 ng/mL (5.9%, 95% CI, 5.5–6.4%). On the other hydrogen peroxide into water.
hand, in 656 patients from the UK [67], baseline Vit D levels Moreover, Se is necessary for phagocytic cells, which
were evaluated in association to COVID-19 mortality. In are a major component of the innate immune system. Insuf-
this study, despite the fact that initially there seemed to be a ficient Se intake reduces the level of phagocytic activity,
clear relationship, after adjusting for confounding variables, which may reduce the oxidative burst as has been observed
no relationship was found with either the risk of developing in neutrophils [30]. In mice, low Se intake has shown to
COVID-19 or mortality, when taking as reference 502,624 inhibit the macrophage phagocytic response by significantly

13
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1609

increasing the expression of inflammatory factors, such as with it, the production of IL-1, IL-2, IL-4, and IFN-ɣ, dis-
iNOS, IL-1β, IL-12, IL-10, PTGe, and NF-κB; meanwhile, turbing the balance of Th1/Th2 profiles which influences
suppression of Se restricts macrophage production of TNFα the isotype change from CD4 + to CD8 + [22]. Zinc signals
[75]. induce tolerogenic dendritic cells by suppressing MHC-II
Associations between the infection, its severity, and the expression and enhancing PD-L1, dampening proinflam-
reported COVID-19 cure rates with the Se status have been matory Th17 and Th9 cells by Treg generation [82]. Zn is
described (Table 1) [76] with cross-sectional studies where involved in the development and function of cells involved in
Se and selenoprotein P have been quantified in samples from innate immunity regulation, such as monocytes, neutrophils,
patients who survived COVID-19, presenting higher con- dendritic cells, and NK cells, and its deficiency affects cell
centrations when compared to non-survivors [41]. One of function and antibody production [83]. The involvement of
the first cross-sectional analyses quantified two important Zn in COVID-19 is related to at least two possible non-
markers of Se status, SELENOP and total serum Se, both exclusive mechanisms. First, Zn is a known structural cofac-
of which were significantly higher in samples from surviv- tor of viral proteins, suggesting that the accessibility of Zn
ing COVID-19 patients compared to non-survivors (Se; ions in infected cells could be a potentially limiting factor in
53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. the virus life cycle. Second, Zn ions are involved in signal
2.1 ± 0.9 mg/L) [41]. In the study by Kocak et al. [77], sig- transduction in the cell and, therefore, in cellular and viral
nificantly higher levels of Se were found in healthy controls gene expression patterns [84]. In patients with COVID-19,
in relation to patients with COVID-19, mostly with moderate low Zn levels have been associated with advanced age, with
manifestations, who had concentrations of 255.23 ± 42.6 ng/ a higher rate of ICU admission and its clinical complica-
dL and with 215.34 ± 49.8 ng/dL, respectively (p > 0.001). tions [5]. Cell culture studies of SARS-CoV and equine
In addition to these reports, Razeghi et al. [3] found a nega- arteritis virus (EAV) have been conducted in combination
tive association between Se and Zn levels with respect to the with Zn2 + and Zn ionophores such as pyrithione (PT),
degree of clinical severity of COVID-19 in a sample of 84 resulting in direct inhibition of the in vitro activity of viral
patients who participated in the study. They found that Se RNA polymerases, preventing RNA elongation in SARS-
levels were below the recommended normal ranges, being CoV [85]. Therefore, this mechanism could be similar in
the patients with severe clinical manifestations the ones that cases of SARS-CoV-2 infection. It has been shown that Zinc
presented the lowest levels, with a mean of 29.86 ± 11.48 ng/ treatment in cells infected with rhinovirus increases the pro-
mL. Several cross-sectional studies show that regardless of duction of interferon α (IFNα) by leukocytes and improves
the degree of severity, once the disease is established, sele- antiviral activity. Considering that downstream signaling
nium levels do not change significantly, being the most rel- of JAK1/STAT1 and the positive regulation of antiviral
evant difference between healthy subjects and those infected enzymes mediate the antiviral effects of IFNα, it is possible
with SARS-CoV-2 [37, 53, 78, 79]. The possible protective that Zn could be favoring this mechanism [42].
effects of Se against COVID-19 could be due to its role as an Zn deficiency in aging and metabolic diseases such as
essential cofactor in selenoproteins that act to reduce ROS diabetes, obesity, and cardiovascular diseases is indirectly
formation, as well as its anti-inflammatory properties by related to susceptibility to COVID-19 [86]. The important
modulating the production of proinflammatory cytokines, role of Zn in immunity and in the viral cell cycle is evident
since both of them are key mechanisms in the pathophysiol- and could have the potential to be studied as an adjuvant
ogy of this infection. treatment for clinical management, seeking to increase anti-
viral resistance. To date, clinical trials related to Zn and
Zinc COVID-19 have presented mixed results (Table 1). The
report by Al-Saleh et al. [53] showed a percentage of 25%
Zinc (Zn) is an essential trace element with important physi- of COVID-19 patients with Zn deficiency (< 0.693 µg/mL).
ological functions such as its participation in growth and the However, when they performed a statistical adjustment to
immune system. Body Zn deficiency is frequently due to include inflammatory markers, no significant correlation was
malabsorption and increased gastrointestinal losses, in addi- found to associate COVID-19 severity with Zn deficiency. In
tion to deficient intake through diet [80]. The lung epithelial contrast, a cross-sectional comparative study reported that
barrier is the first to be exposed to respiratory viruses. It serum Zn levels decreased (median 56.61 µg/dL, n = 200)
has been shown that Zn deficiency alters epithelial barrier in relation to disease severity, with the most reduced values
function through positive regulation of IFN-ɣ and TNF-ɑ, in severe COVID-19 patients [87]. This result agreed with
but also enhances FasR signaling and apoptosis so that Zn those of Jothimani et al. [88] who found significantly lower
supplementation could prevent or decrease apoptosis [81]. Zn levels in COVID-19 patients (n = 47) when compared
Also, Zn deficiency modifies cellular functions that affect to healthy controls (n = 45) (74.5 µg/dl (IQR 53.4–94.6 µg/
the immune response, for example, it affects Th1 cells and, dl) vs. 105.8 µg/dl (IQR 95.65–120.90 µg/dl), p < 0.001).

13
1610 R.-B. N. Renata et al.

Similarly, in a retrospective cohort study conducted in circulating neutrophils and their capacity to generate super-
China, they found a high correlation coefficient of severe oxide anion [99]. On viral infections and upon initiation of
COVID-19 disease with different transition metals, espe- the oxidative response by ROS, Cu downregulates NF-κB
cially Zn, magnesium, and iron (CC: 0.64 for iron-zinc; CC: expression, causing suppression of inflammatory cytokines,
0.55 for iron-magnesium; CC: 0.51 for iron-manganese) chemokines, and adhesion molecules [100]. Cu dietary defi-
[89]. The aforementioned clinical studies present interesting ciency has been examined in humans and has been associ-
findings that establish relevance to critical proteins involved ated with the proliferation of peripheral blood mononuclear
in the antiviral immune response and containing zinc in their cells [101]. A meta-analysis of Cu consumption associated
structure, mainly those that disrupt virus replication. Fur- the occurrence of recurrent respiratory tract infections in
ther investigation of this trace element in controlled trials Chinese children with immune function, genetic factors, and
will be necessary to verify the association between Zn and nutritional status. Among the results of this study, Zn and
COVID-19. Cu deficiency may be contributing factors to children’s sus-
ceptibility to respiratory infections [102]. Another group of
Copper researchers determined the presence of Cu by CP quantifica-
tion in serum samples from patients with COVID-19, find-
Copper (Cu) is an essential micronutrient with two main bio- ing that surviving patients had higher serum concentrations
logical functions, the first as a structural/catalytic cofactor of of Cu and CP compared to non-survivors [103]. There is a
enzymes, and the second as a coactivator of key transcrip- relationship between trace elements Zn and Cu due to their
tion factors [90]. Cu serves as a cofactor when present as an antagonistic behavior and competitive absorption relation-
ion and is used in redox enzymatic reactions [91] or carry- ship. When Zn intake is exceeded for prolonged periods,
ing out other functions such as the metabolism of biologi- it can contribute to a Cu deficiency and vice versa [100].
cal amines, activation of neuropeptides, or cell respiration Al-Saleh et al. [53] describe a 1:1 Cu/Zn ratio in healthy
(cytochrome-c oxidase). Also, Cu has been linked to sele- adults and in COVID-19 patients from their study; this ratio
noprotein expression in animal models where it suppresses remained high (Cu/Zn > 1.5 + –0.63, 83%), a result that sig-
the mRNA levels of GPX1 selenoprotein and selenoprotein nificantly correlated with C-reactive protein, an indicator
W, generally reducing the enzymatic activity of GPX and of inflammation. A similar result was obtained by Skalny
thyroxine reductase (TXNRD). This effect is achieved by et al. [42] who showed an increase of up to 45% in the Cu/Zn
decreasing the coding efficiency of the UGA codon in the ratio in the case of disease with mild symptoms compared
cell but has been little explored and for this reason it is not to patients with moderate symptoms, suggesting that this
conclusive [92]. Ceruloplasmin ferroxidase (CP) accounts ratio could be a biomarker associated with exacerbation of
for the majority of circulating Cu and serves as a transport an inflammatory process derived from the infection. In con-
protein. These data suggest that Cu has specific functions trast, in the study by Kocak et al., [76] no differences were
in viral replication in the cytoplasm, as well as in the inter- found when comparing this ratio between people positive for
actions of viral proteins with the secretory pathway [93]. SARS-CoV-2 with healthy people (see Table 1).
On the other hand, copper neutralizes toxic ROS as part As a result of the COVID-19 pandemic, there was an
of cytosolic and extracellular Cu(II)/Zn(II) superoxide dis- increase in the uncontrolled consumption of multivitamins,
mutases (SOD1 and SOD3) [94]. Hence, its protective role so there is a strong possibility of Cu deficiencies in people
against viral diseases is decisive. During the first stage of with COVID-19 who consumed Zn supplements without
H5N1 influenza virus replication, virus-induced disruption supervision. As an essential micronutrient, Cu is required
of cytosolic Cu/Zn-SOD formation [95] unbalances the oxi- for the maintenance of biological mechanisms and cel-
dative process and ATP7A, a protein that imports [Cu1 +] lular homeostasis; therefore, it is necessary to maintain a
into trans-Golgi–derived compartments, is required for the balance and avoid both its deficiency and its excess, since
synthesis of influenza viral RNA and proteins [96]. In vitro there are no conclusive studies relating it to the severity of
studies show a link between host proteins that transport Cu COVID-19.
into the cell (CTR1) and the secretory pathway (ATP7A),
with their role in influenza A (H1N1) virus protein and RNA
synthesis [90]. Perspectives
Regarding immune function, Cu is an important factor
for the proper functionality of immune cells such as B cells, The enormous impact that the COVID-19 pandemic has had
T-helper cells, NK cells, neutrophils, and macrophages. worldwide is due, in part, to the nutritional deficiency of the
Cu transport genes have been implicated in macrophage- population. We have gone through an era of technological,
mediated host defense [97, 98], its deficiency reduces IL-2 epidemiological, and nutritional transition, where, regard-
and T-cell proliferation, as well as reducing the number of less of the benefits, we also faced the greatest challenges in

13
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1611

public health. The consumption of low micronutrient foods, sonal relationships that could have appeared to influence the work
but fat- and carbohydrate-dense, along with a sedentary life- reported in this paper.
style has increased the prevalence of non-communicable dis-
eases, such as obesity, diabetes, and hypertension. In addi-
tion to the negative medium and long-term effects of these References
diseases, the limited consumption of micronutrients causes a
weakening of the immune system function and, therefore, a 1. WHO Coronavirus (COVID-19) Dashboard. https://​covid​19.​
greater susceptibility to developing infections. On the other who.​int. Accessed 28 Apr 2022
2. Alexander J, Tinkov A, Strand TA, Alehagen U, Skalny A,
hand, famine has not been eradicated; hence, energy- and Aaseth J (2020) Early nutritional interventions with zinc, sele-
micronutrient-deficient diets predispose a large amount of nium and vitamin D for raising anti-viral resistance against
the world’s population to disease. progressive COVID-19. Nutrients 12:2358
The pandemic arrived at a moment of global vulnerabil- 3. Razeghi Jahromi S, Moradi Tabriz H, Togha M et al (2021)
The correlation between serum selenium, zinc, and COVID-19
ity, so it is important to highlight the need to acquire the severity: an observational study. BMC Infect Dis 21:899
habits for a healthy diet, where there is an optimal consump- 4. Jovic TH, Ali SR, Ibrahim N, Jessop ZM, Tarassoli SP, Dobbs
tion of micronutrients in variety, quality, and quantity. An TD, Holford P, Thornton CA, Whitaker IS (2020) Could vita-
unbalanced diet is not the only risk factor that predisposes mins help in the fight against COVID-19? Nutrients 12:2550
5. Tomasa-Irriguible T-M, Bielsa-Berrocal L, Bordejé-Laguna
an individual to develop the disease, but it does have many L, Tural-Llàcher C, Barallat J, Manresa-Domínguez J-M,
beneficial effects regarding prevention, or it could even Torán-Monserrat P (2021) Low levels of few micronutrients
accelerate the recovery of patients by the use of micronutri- may impact COVID-19 disease progression: an observational
ent supplementation. study on the first wave. Metabolites 11:565
6. Fact sheets - Malnutrition. https://​www.​who.​int/​news-​room/​
fact-​sheets/​detail/​malnu​triti​on. Accessed 25 Apr 2022
7. Barazzoni R, Gortan Cappellari G (2020) Double burden of
malnutrition in persons with obesity. Rev Endocr Metab Disord
Conclusion 21:307–313
8. Yang H, Rao Z (2021) Structural biology of SARS-CoV-2 and
implications for therapeutic development. Nat Rev Microbiol
There is scientific evidence supporting the relationship 19:685–700
between micronutrient status and the response against 9. Devaux CA, Rolain J-M, Raoult D (2020) ACE2 receptor poly-
SARS-CoV-2, as a crucial factor that influences the clinical morphism: susceptibility to SARS-CoV-2, hypertension, multi-
organ failure, and COVID-19 disease outcome. J Microbiol
severity of COVID-19, mainly through immunomodulatory Immunol Infect 53:425–435
and antioxidant mechanisms. The cohort and observational 10. Santopolo S, Riccio A, Santoro MG (2021) The biogenesis
studies carried out to date support a relationship between of SARS-CoV-2 spike glycoprotein: multiple targets for host-
nutritional status and COVID-19, based on biological gradi- directed antiviral therapy. Biochem Biophys Res Commun
538:80–87
ent, plausibility, analogy, and temporality. However, in order 11. V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V (2021)
to confirm a causal relationship to the severity of the disease Coronavirus biology and replication: implications for SARS-
and/or mortality, it is necessary to carry out more clinical CoV-2. Nat Rev Microbiol 19:155–170
trials to demonstrate it and to explore its involvement in the 12. Jack A, Ferro LS, Trnka MJ et al (2021) SARS-CoV-2 nucle-
ocapsid protein forms condensates with viral genomic RNA.
antiviral response. PLOS Biol 19:e3001425
13. Mu J, Xu J, Zhang L et al (2020) SARS-CoV-2-encoded nucle-
Acknowledgements RBNR thanks Consejo Nacional de Ciencia y ocapsid protein acts as a viral suppressor of RNA interference
Tecnología (CONACYT) for her Ph.D. scholarship. The authors are in cells. Sci China Life Sci 63:1413–1416
grateful to Mejía-León AM for editing the figure. 14. Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM,
Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado
Author Contribution All authors contributed to the study concep- R, Torres J, Aguilella VM, Enjuanes L (2015) Severe acute
tion and design. Material preparation, data collection, and analysis respiratory syndrome coronavirus E protein transports cal-
were performed by Roldán-Bretón Nuria Renata. The first draft of the cium ions and activates the NLRP3 inflammasome. Virology
manuscript was written by Roldán-Bretón Nuria Renata and Mejía- 485:330–339
León María Esther. González-Rascón Anna Arely and Leija-Montoya 15. Liang K-H, Chiang P-Y, Ko S-H et al (2021) Antibody cocktail
Ana Gabriela commented and participated on previous versions of the effective against variants of SARS-CoV-2. J Biomed Sci 28:80
manuscript. All authors read and approved the final manuscript. 16. Mengist HM, Kombe Kombe AJ, Mekonnen D, Abebaw A,
Getachew M, Jin T (2021) Mutations of SARS-CoV-2 spike
protein: implications on immune evasion and vaccine-induced
Declarations immunity. Semin Immunol 101533
17. Yang L, Li J, Guo S et al (2021) SARS-CoV-2 variants, RBD
Competing Interests RBNR receives a CONACYT grant number mutations, binding affinity, and antibody escape. Int J Mol Sci
2021–000018-02NACF-06760 to pursue doctoral studies. The authors 22:12114
declare that they have no known competing financial interests or per-

13
1612 R.-B. N. Renata et al.

18. Liu H, Wei P, Zhang Q, et al (2021) 501Y.V2 and 501Y.V3 var- 37. Im JH, Je YS, Baek J, Chung M-H, Kwon HY, Lee J-S (2020)
iants of SARS-CoV-2 lose binding to bamlanivimab in vitro. Nutritional status of patients with COVID-19. Int J Infect Dis
mAbs 13:1919285 100:390–393
19. Hu B, Guo H, Zhou P, Shi Z-L (2020) Characteristics of SARS- 38. Wee AKH (2021) COVID-19’s toll on the elderly and those with
CoV-2 and COVID-19. Nat Rev Microbiol 1–14 diabetes mellitus – is vitamin B12 deficiency an accomplice?
20. Wang M-Y, Zhao R, Gao L-J, Gao X-F, Wang D-P, Cao Med Hypotheses 146:110374
J-M (2020) SARS-CoV-2: structure, biology, and structure- 39. D’Avolio A, Avataneo V, Manca A, Cusato J, De Nicolò A, Luc-
based therapeutics development. Front Cell Infect Microbiol chini R, Keller F, Cantù M (2020) 25-hydroxyvitamin D concen-
10:587269 trations are lower in patients with positive PCR for SARS-CoV-2.
21. Wu Z, McGoogan JM (2020) Characteristics of and impor- Nutrients 12:1359
tant lessons from the coronavirus disease 2019 (COVID-19) 40. Hastie CE, Mackay DF, Ho F et al (2020) Vitamin D concentra-
outbreak in China: summary of a report of 72 314 cases from tions and COVID-19 infection in UK Biobank. Diabetes Metab
the Chinese Center for Disease Control and Prevention. JAMA Syndr 14:561–565
323:1239–1242 41. Moghaddam A, Heller RA, Sun Q et al (2020) Selenium defi-
22. Sadeghsoltani F, Mohammadzadeh I, Safari M-M, Hassanpour ciency is associated with mortality risk from COVID-19. Nutri-
P, Izadpanah M, Qujeq D, Moein S, Vaghari-Tabari M (2021) ents 12:E2098
Zinc and respiratory viral infections: important trace element in 42. Skalny AV, Rink L, Ajsuvakova OP et al (2020) Zinc and respira-
anti-viral response and immune regulation. Biol Trace Elem Res tory tract infections: perspectives for COVID-19 (Review). Int J
1–16 Mol Med 46:17–26
23. Vaghari-Tabari M, Mohammadzadeh I, Qujeq D, Majidinia M, 43. Fedele D, De Francesco A, Riso S, Collo A (2021) Obesity, mal-
Alemi F, Younesi S, Mahmoodpoor A, Maleki M, Yousefi B, nutrition, and trace element deficiency in the coronavirus disease
Asemi Z (2021) Vitamin D in respiratory viral infections: a key (COVID-19) pandemic: an overview. Nutr Burbank Los Angel
immune modulator? Crit Rev Food Sci Nutr 1–16 Cty Calif 81:111016
24. Merad M, Subramanian A, Wang TT (2021) An aberrant 44. Ragasa C, Lambrecht I, Mahrt K, Zhao H, Aung ZW, Scott J
inflammatory response in severe COVID-19. Cell Host Microbe (2021) Can nutrition education mitigate the impacts of COVID-
29:1043–1047 19 on dietary quality? Cluster-randomised controlled trial
25. Braciale TJ, Sun J, Kim TS (2012) Regulating the adaptive evidence in Myanmar’s Central Dry Zone. Matern Child Nutr
immune response to respiratory virus infection. Nat Rev Immu- 17:e13259
nol 12:295–305 45. Zhou Y, Chi J, Lv W, Wang Y (2021) Obesity and diabetes as
26. Yoshida S, Ono C, Hayashi H, Fukumoto S, Shiraishi S, Tomono high-risk factors for severe coronavirus disease 2019 (Covid-19).
K, Arase H, Matsuura Y, Nakagami H (2021) SARS-CoV-2-in- Diabetes Metab Res Rev 37:e3377
duced humoral immunity through B cell epitope analysis in 46. Huang Z, Liu Y, Qi G, Brand D, Zheng SG (2018) Role of vita-
COVID-19 infected individuals. Sci Rep 11:5934 min A in the immune system. J Clin Med 7:258
27. Khatiwada S, Subedi A (2021) A mechanistic link between sele- 47. Stephensen CB, Lietz G (2021) Vitamin A in resistance to and
nium and coronavirus disease 2019 (COVID-19). Curr Nutr Rep recovery from infection: relevance to SARS-CoV2. Br J Nutr
10:125–136 126:1663–1672
28. Keles ES (2020) Mild SARS-CoV-2 infections in children might 48. Elmadfa I, Meyer AL (2019) The role of the status of selected
be based on evolutionary biology and linked with host reactive micronutrients in shaping the immune function. Endocr Metab
oxidative stress and antioxidant capabilities. New Microbes New Immune Disord Drug Targets 19:1100–1115
Infect 36:100723 49. Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda
29. Kozlov EM, Ivanova E, Grechko AV, Wu W-K, Starodubova H, La Frano MR, Bohn T (2020) Strengthening the immune sys-
AV, Orekhov AN (2021) Involvement of oxidative stress and the tem and reducing inflammation and oxidative stress through diet
innate immune system in SARS-CoV-2 infection. Diseases 9:17 and nutrition: considerations during the COVID-19 crisis. Nutri-
30. Laforge M, Elbim C, Frère C, Hémadi M, Massaad C, Nuss ents 12:E1562
P, Benoliel J-J, Becker C (2020) Tissue damage from neutro- 50. Zhang Y, Du Z, Ma W, Chang K, Zheng C (2020) Vitamin A
phil-induced oxidative stress in COVID-19. Nat Rev Immunol status and recurrent respiratory infection among Chinese chil-
20:515–516 dren: a nationally representative survey. Asia Pac J Clin Nutr
31. Checconi P, De Angelis M, Marcocci ME, Fraternale A, Magnani 29:566–576
M, Palamara AT, Nencioni L (2020) Redox-modulating agents 51. Tepasse P-R, Vollenberg R, Fobker M, Kabar I, Schmidt H,
in the treatment of viral infections. Int J Mol Sci 21:4084 Meier JA, Nowacki T, Hüsing-Kabar A (2021) Vitamin A plasma
32. Abouhashem AS, Singh K, Azzazy HME, Sen CK (2020) Is levels in COVID-19 patients: a prospective multicenter study and
low alveolar type II cell SOD3 in the lungs of elderly linked hypothesis. Nutrients 13:2173
to the observed severity of COVID-19? Antioxid Redox Signal 52. Sarohan AR (2020) COVID-19: endogenous retinoic acid
33:59–65 theory and retinoic acid depletion syndrome. Med Hypotheses
33. Luo X-H, Zhu Y, Mao J, Du R-C (2021) T cell immunobiology 144:110250
and cytokine storm of COVID-19. Scand J Immunol 93:e12989 53. Al-Saleh I, Alrushud N, Alnuwaysir H, Elkhatib R, Shoukri M,
34. Ni L, Ye F, Cheng M-L et al (2020) Detection of SARS-CoV- Aldayel F, Bakheet R, Almozaini M (2022) Essential metals,
2-specific humoral and cellular immunity in COVID-19 conva- vitamins and antioxidant enzyme activities in COVID-19 patients
lescent individuals. Immunity 52:971-977.e3 and their potential associations with the disease severity. Biomet-
35. Zhu N, Zhang D, Wang W et al (2020) A novel coronavirus als 35:125–145
from patients with pneumonia in China, 2019. N Engl J Med 54. Lindschinger M, Tatzber F, Schimetta W, Schmid I, Lindsch-
382:727–733 inger B, Cvirn G, Stanger O, Lamont E, Wonisch W (2019) A
36. Rodda LB, Netland J, Shehata L et al (2021) Functional SARS- randomized pilot trial to evaluate the bioavailability of natural
CoV-2-specific immune memory persists after mild COVID-19. versus synthetic vitamin b complexes in healthy humans and their
Cell 184:169-183.e17 effects on homocysteine, oxidative stress, and antioxidant levels.
Oxid Med Cell Longev 2019:6082613

13
Immunomodulatory Role of Microelements in COVID‑19 Outcome: a Relationship with Nutritional… 1613

55. Batista KS, Cintra VM, Lucena PAF, Manhães-de-Castro R, Tos- protease target host selenoproteins and glutathione synthesis?
cano AE, Costa LP, Queiroz MEBS, de Andrade SM, Guzman- Front Nutr 7:143
Quevedo O, Aquino J de S (2022) The role of vitamin B12 in 72. Zhang J, Saad R, Taylor EW, Rayman MP (2020) Selenium
viral infections: a comprehensive review of its relationship with and selenoproteins in viral infection with potential relevance to
the muscle-gut-brain axis and implications for SARS-CoV-2 COVID-19. Redox Biol 37:101715
infection. Nutr Rev 80:561–578 73. Bermano G, Méplan C, Mercer DK, Hesketh JE Selenium and
56. Lai Y-J, Chang H-S, Yang Y-P, Lin T-W, Lai W-Y, Lin Y-Y, viral infection: are there lessons for COVID-19? Br J Nutr 1–10
Chang C-C (2021) The role of micronutrient and immunomod- 74. Seale LA, Torres DJ, Berry MJ, Pitts MW (2020) A role for
ulation effect in the vaccine era of COVID-19. J Chin Med selenium-dependent GPX1 in SARS-CoV-2 virulence. Am J
Assoc 84:821–826 Clin Nutr 112:447–448
57. Deschasaux-Tanguy M, Srour B, Bourhis L et al (2021) Nutri- 75. Xu J, Gong Y, Sun Y, Cai J, Liu Q, Bao J, Yang J, Zhang Z
tional risk factors for SARS-CoV-2 infection: a prospective (2020) Impact of selenium deficiency on inflammation, oxi-
study within the NutriNet-Santé cohort. BMC Med 19:290 dative stress, and phagocytosis in mouse macrophages. Biol
58. Itelman E, Wasserstrum Y, Segev A et al (2020) Clinical char- Trace Elem Res 194:237–243
acterization of 162 COVID-19 patients in Israel: preliminary 76. Zhang J, Taylor EW, Bennett K, Saad R, Rayman MP (2020)
report from a large tertiary center. Isr Med Assoc J IMAJ Association between regional selenium status and reported
22:271–274 outcome of COVID-19 cases in China. Am J Clin Nutr
59. Tan CW, Ho LP, Kalimuddin S et al (2020) Cohort study to 111:1297–1299
evaluate the effect of vitamin D, magnesium, and vitamin B12 in 77. Kocak OF, Ozgeris FB, Parlak E, Kadıoglu Y, Yuce N, Yaman
combination on progression to severe outcomes in older patients ME, Bakan E (2021) Evaluation of serum trace element levels
with coronavirus (COVID-19). Nutr Burbank Los Angel Cty and biochemical parameters of COVID-19 patients according
Calif 79–80:111017 to disease severity. Biol Trace Elem Res. https://​doi.​org/​10.​
60. Carpagnano GE, Di Lecce V, Quaranta VN, Zito A, Buonamico 1007/​s12011-​021-​02946-1
E, Capozza E, Palumbo A, Di Gioia G, Valerio VN, Resta O 78. Alkattan A, Alabdulkareem K, Kamel A, Abdelseed H,
(2021) Vitamin D deficiency as a predictor of poor prognosis Almutairi Y, Alsalameen E Correlation between micronutri-
in patients with acute respiratory failure due to COVID-19. J ent plasma concentration and disease severity in COVID-19
Endocrinol Invest 44:765–771 patients. Alex J Med 57:21–27
61. Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A (1950) 79. Bagher Pour O, Yahyavi Y, Karimi A, Khamaneh AM, Milani
Hunninghake GW (2010) Vitamin D decreases RSV induction M, Khalili M, Sharifi A (2021) Serum trace elements levels
of NF-κB-linked chemokines and cytokines in airway epithe- and clinical outcomes among Iranian COVID-19 patients. Int
lium while maintaining the antiviral state. J Immunol Baltim Md J Infect Dis 111:164–168
184:965–974 80. Livingstone C (2015) Zinc. Nutr Clin Pract 30:371–382
62. Zheng S, Yang J, Hu X, Li M, Wang Q, Dancer RCA, Parekh D, 81. Bao S, Knoell DL (2006) Zinc modulates cytokine-induced
Gao-Smith F, Thickett DR, Jin S (2020) Vitamin D attenuates lung epithelial cell barrier permeability. Am J Physiol Lung
lung injury via stimulating epithelial repair, reducing epithelial Cell Mol Physiol 291:L1132-1141
cell apoptosis and inhibits TGF-β induced epithelial to mesen- 82. Wessels I, Maywald M, Rink L (2017) Zinc as a gatekeeper of
chymal transition. Biochem Pharmacol 177:113955 immune function. Nutrients 9:1286
63. Baktash V, Hosack T, Patel N, Shah S, Kandiah P, Van Den 83. Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K, Librowski T
Abbeele K, Mandal AKJ, Missouris CG (2020) Vitamin D status (2017) Antioxidant and anti-inflammatory effects of zinc. Zinc-
and outcomes for hospitalised older patients with COVID-19. dependent NF-κB signaling. Inflammopharmacology 25:11–24
Postgrad Med J postgradmedj-2020–138712 84. Lazarczyk M, Favre M (2008) Role of Zn2+ ions in host-virus
64. Panagiotou G, Tee SA, Ihsan Y, et al (2020) Low serum 25‐ interactions. J Virol 82:11486–11494
hydroxyvitamin D (25[OH]D) levels in patients hospitalised 85. te Velthuis AJW, van den Worm SHE, Sims AC, Baric RS,
with COVID‐19 are associated with greater disease severity. Snijder EJ, van Hemert MJ (2010) Zn2+ inhibits coronavirus
Clin Endocrinol (Oxf) https://​doi.​org/​10.​1111/​cen.​14276 and arterivirus RNA polymerase activity in vitro and zinc iono-
65. Mercola J, Grant WB, Wagner CL (2020) Evidence regarding phores block the replication of these viruses in cell culture.
vitamin D and risk of COVID-19 and its severity. Nutrients PLoS Pathog 6:e1001176
12:E3361 86. Mayor-Ibarguren A, Busca-Arenzana C, Robles-Marhuenda Á
66. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF (2020) (2020) A hypothesis for the possible role of zinc in the immu-
SARS-CoV-2 positivity rates associated with circulating nological pathways related to COVID-19 infection. Front
25-hydroxyvitamin D levels. PLoS ONE 15:e0239252 Immunol 11:1736
67. Hastie CE, Pell JP, Sattar N (2021) Vitamin D and COVID-19 87. PVSN KK, Tomo S, Purohit P, et al (2022) Comparative
infection and mortality in UK Biobank. Eur J Nutr 60:545–548 analysis of serum zinc, copper and magnesium level and their
68. Rodríguez Tort A, Montelongo Mercado EA, Martínez-Cuazitl relations in association with severity and mortality in SARS-
A, Puente Nieto AV, Adriana Reyes Pérez R (2020) La defi- CoV-2 patients. Biol Trace Elem Res 1–8
ciencia de vitamina D es un factor de riesgo de mortalidad en 88. Jothimani D, Kailasam E, Danielraj S et al (2020) COVID-19:
pacientes con COVID-19. Rev Sanid Mil 74 poor outcomes in patients with zinc deficiency. Int J Infect Dis
69. Beck MA, Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, IJID Off Publ Int Soc Infect Dis 100:343–349
Barclay D, Levander OA (2001) Selenium deficiency increases 89. Zeng H, Yang Q, Yuan P, Wang X, Cheng L (2021) Associa-
the pathology of an influenza virus infection. FASEB J Off Publ tions of essential and toxic metals/metalloids in whole blood
Fed Am Soc Exp Biol 15:1481–1483 with both disease severity and mortality in patients with
70. Avery JC, Hoffmann PR (2018) Selenium, selenoproteins, and COVID-19. FASEB J 35:e21392
immunity. Nutrients. https://​doi.​org/​10.​3390/​nu100​91203 90. Puchkova LV, Kiseleva IV, Polishchuk EV, Broggini M, Ily-
71. Taylor EW, Radding W (2020) Understanding selenium and glu- echova EYu (2021) The crossroads between host copper metab-
tathione as antiviral factors in COVID-19: does the viral Mpro olism and influenza infection. Int J Mol Sci 22:5498

13
1614 R.-B. N. Renata et al.

91. Govind V, Bharadwaj S, Sai Ganesh MR, Vishnu J, Shankar 98. Stafford SL, Bokil NJ, Achard MES, Kapetanovic R, Schembri
KV, Shankar B, Rajesh R (2021) Antiviral properties of copper MA, McEwan AG, Sweet MJ (2013) Metal ions in macrophage
and its alloys to inactivate COVID-19 virus: a review. Biomet- antimicrobial pathways: emerging roles for zinc and copper.
als 1–19 Biosci Rep 33:e00049
92. Schwarz M, Lossow K, Schirl K, Hackler J, Renko K, Kopp 99. Percival S (1998) Copper and immunity. Am J Clin Nutr. https://​
JF, Schwerdtle T, Schomburg L, Kipp AP (2020) Copper inter- doi.​org/​10.​1093/​ajcn/​67.5.​1064S
feres with selenoprotein synthesis and activity. Redox Biol 100. Rani I, Goyal A, Bhatnagar M, Manhas S, Goel P, Pal A, Prasad
37:101746 R (2021) Potential molecular mechanisms of zinc- and copper-
93. Jonathan C. Rupp ML (2017) Host cell copper transporters CTR1 mediated antiviral activity on COVID-19. Nutr Res N Y N
and ATP7A are important for influenza A virus replication. Virol 92:109–128
J. https://​doi.​org/​10.​1186/​s12985-​016-​0671-7 101. Kelley DS, Daudu PA, Taylor PC, Mackey BE, Turnlund JR
94. Linder MC (2020) Copper homeostasis in mammals, with (1995) Effects of low-copper diets on human immune response.
emphasis on secretion and excretion. a review. Int J Mol Sci Am J Clin Nutr 62:412–416
21:4932 102. Mao S, Zhang A, Huang S (2014) Meta-analysis of Zn, Cu and
95. Lin X, Wang R, Zou W, Sun X, Liu X, Zhao L, Wang S, Jin Fe in the hair of Chinese children with recurrent respiratory tract
M (2016) The influenza virus H5N1 infection can induce ROS infection. Scand J Clin Lab Invest 74:561–567
production for viral replication and host cell death in A549 cells 103. Hackler J, Heller RA, Sun Q, Schwarzer M, Diegmann J, Bach-
modulated by human Cu/Zn superoxide dismutase (SOD1) over- mann M, Moghaddam A, Schomburg L (2021) Relation of serum
expression. Viruses 8:13 copper status to survival in COVID-19. Nutrients 13:1898
96. Influenza versus host: the role of novel copper‐related host fac-
tors in antiviral immunity - Dagdag - 2020 - The FASEB Jour- Publisher's Note Springer Nature remains neutral with regard to
nal - Wiley Online Library. https://faseb.onlinelibrary.wiley.com/ jurisdictional claims in published maps and institutional affiliations.
doi/https://d​ oi.o​ rg/1​ 0.1​ 096/f​ asebj.2​ 020.3​ 4.s​ 1.0​ 6545. Accessed 1
May 2022
97. Raha S, Mallick R, Basak S, Duttaroy AK (2020) Is copper ben-
eficial for COVID-19 patients? Med Hypotheses 142:109814

13