Selenium Plays A Key Role During SARS-Cov-2 Infections

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A new study by researchers from Florida International University, Miami-USA has found that Selenium plays an important role in the human host during viral infections including those by the SARS-Cov-2 coronavirus, assisting in redox homeostasis, antioxidant defense, and minimizing oxidative stress.

The ongoing COVID-19 pandemic has put a spotlight on the need to review the evidence on the impact of nutritional strategies to maintain a healthy immune system, particularly in instances where there are limited therapeutic treatments.
 
Selenium, an essential trace element in humans, has a long history of lowering the occurrence and severity of viral infections. Much of the benefits derived from selenium are due to its incorporation into selenocysteine, an important component of proteins known as selenoproteins. Viral infections are associated with an increase in reactive oxygen species and may result in oxidative stress.
 
Studies suggest that selenium deficiency alters immune response and viral infection by increasing oxidative stress and the rate of mutations in the viral genome, leading to an increase in pathogenicity and damage to the host. This review examines viral infections, including the novel SARS-CoV-2, in the context of selenium, in order to inform potential nutritional strategies to maintain a healthy immune system.
 
The study findings were published in the peer reviewed International Journal of Molecular Sciences. https://www.mdpi.com/1422-0067/23/1/280

Viral infections have afflicted human health despite great advancements in scientific knowledge and technologies [1,2,3]. Most recently, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 200 million individuals during 2019–August 2021 and has led to over 4.4 million deaths globally [4].

Selenium (Se), an essential trace element in humans, has a long history of lowering the occurrence and severity of viral infections [5,6,7,8,9]. Se deficiency impacts immune function [10], viral expression [8], selenoprotein expression [11], and alters antioxidant response [12], allowing for greater susceptibility to severe viral and bacterial infections [13].

Supplementing the diet with Se has demonstrated positive effects on enhancing immunity against viral attacks [5]. Much of the benefits derived from Se are due to its incorporation into selenocysteine, an important component of the antioxidant defense systems, including the regulation of glutathione peroxidase (GPXs) and thioredoxin reductase (TXNRD) activities [14].

Low levels of Se can lead to more severe forms of viral infections and adequate selenium levels may provide a protective effect toward the host response by affecting both immune response and oxidative stress [13,15]. Severe pathology in Se deficiency is evidenced by more frequent and graver symptoms, higher viral loads, declining levels of antioxidant enzymes such as GPX, and mutations to the viral genome.

Studies conducted by Beck et al. described in this review, demonstrate that Se-deficiency is capable of increasing the virulence of a benign coxsackie virus through viral mutations and these mutations have led to a reduction in GPX activity, therefore, resulting in oxidative stress [13,15].

The current coronavirus (COVID-19) infection pandemic has put a spotlight on the need to review the evidence on the impact of nutritional strategies to maintain a healthy immune system, as there are limited therapeutic treatments. Therefore, this review principally focuses on Se, in the context of viral infections, including the novel SARS-CoV-2. A review of the most common selenoproteins and their functions will be followed by the evidence on the role and impact of Se on the human host’s ability to battle viral infections.

Selenoproteins and Functions

Selenoproteins are proteins that have incorporated the 21st amino acid in the genetic code, selenocysteine (Sec) into their polypeptide chain. Selenocysteine is a true proteinogenic amino acid in that it has its own unique codon (UGA), Sec insertion sequence (SECIS), Sec-specific elongation factor (eEFsec), transfer RNA (tRNASec), and is co-translationally inserted [16]. The biological functions of Se are mostly exerted through selenoprotein domains that contain Sec residues [17,18]. Twenty-four selenoprotein genes have been characterized in mice and 25 in humans [19,20].

Some of these selenoproteins demonstrated their essential roles in developmental processes and in disease pathogenesis [21,22]. Selenoproteins have been classified based on their known or suspected cellular functions; for example GPX 1–4 for antioxidation, TXNRD 1–3, methionine sulfoxide reductase B (MSRB)1, selenoproteins (SELENO) H, M, and W for redox regulation, iodothyronine deiodinase (DIO) 1–3 for thyroid hormone metabolism, SELENOP for selenium transport and storage, selenophosphate synthetase (SEPHS) 2 for the synthesis of selenophosphate, SELENOK and T for calcium metabolism, SELENON protein involved in myogenesis, SELENOF, I and S for protein folding, and SELENOO protein with AMPylation activity [21,22].

Only 2 of the 25 selenoproteins identified are extracellular, selenoprotein P (SELENOP), and extracellular glutathione peroxidase (GPX3) [23]. SELENOP is noteworthy in that it carries out the crucial role of distributing Se in plasma from the liver where dietary selenium is metabolized [24,25]. and contains up to 9 Sec residues [23]. S

ELENOP then binds to apolipoprotein E receptor-2 (apoER2) receptors on various tissues including the brain and testis or lipoprotein receptor megalin (Lrp2) for endocytosis in the kidneys for systemic distribution [18,26]. Different isoforms of SELENOP confer specificity to the various receptors [26]. Once endocytosed, Se can be used for the formation of other selenoproteins.

Among the more well-studied selenoproteins are those involved in maintaining homeostatic redox states, namely GPXs. There are 5 isoforms of GPXs that contain selenocysteine residues and they each occupy distinct regions of the cell. Each GPX isoform catalyzes the reduction of hydrogen peroxides using glutathione (GSH) as a cofactor, and in doing so, maintains cellular homeostasis. In this capacity, GPXs play a vital role not only in the prevention of oxidative stress but also in regulating redox signaling that can have broader effects on cell proliferation, apoptosis, and cytokine expression [27].

This important role of GPX and dietary Se is highlighted by the work of Beck et al., described later in this review, which demonstrated that Se-deficient mice were susceptible to a myocarditic strain of coxsackievirus whereas Se-adequate mice were unperturbed [10,28]. It was hypothesized that diminished activity of GPX was responsible for viral mutations in the Se-deficient mice and the production of more pathogenic virions [10,28].

Thioredoxin reductases (TXNRDs) are a family of selenoproteins, whose main function is to reduce thioredoxins but has broad specificity allowing it to reduce other endogenous and exogenous substrates [18,29]. The reduction of TXNRD’s is accomplished by electrons from nicotinamide adenine dinucleotide phosphate (NADPH), which are transferred to the active site of TXNRDs via flavin adenine dinucleotide (FAD), a redox-active coenzyme [18,29].

Thioredoxins themselves reduce a number of small proteins including transcription factors such as nuclear factor kappa beta (NF-κβ), p53, redox factor 1 (REF-1), apurinic/apyrimidinic endonucleases 1 (AP-1), and phosphatase and tensin homologue deleted on chromosome ten (PTEN) thereby controlling the expression of various genes involved in cell growth, proliferation and inflammation [30].

Methionine sulfoxide reductase (MSR) is yet another selenoprotein with enzymatic activity that combats intercellular oxidative damage [18,31,32,33]. Specifically, MSR reduces the oxidized sulfur of methionine sulfoxide to produce the amino acid methionine [18,31,32,33].

Methionine sulfoxide alters protein function, may cause misfolding and dysregulates key cellular processes [33]. Lee et al. [32] demonstrated that MSRB1 is involved in cytokine regulation in macrophages by promoting the expression of anti-inflammatory cytokines IL-10 and IL-1RA. Coincidently, MSRB1 is the only methionine sulfoxide reductase that is a selenoprotein [32].

Unlike the aforementioned selenoproteins, SELENOK does not participate directly in redox reactions [34]. Instead SELENOK, a disordered endoplasmic reticulum transmembrane protein is reliant on partner proteins to form complexes and execute various functions [34]. One of the most well-established roles of SELENOK is in the palmitoylation of various substrates when complexed with the acyltransferase DHHC6 [34]. One target of the SELENOK/DHHC6 complex is inositol 1,4,5-trisphosphate receptor, an endoplasmic reticulum (ER) calcium channel protein that is stabilized once acylated [34]. SELENOK, therefore, plays a role in maintaining calcium efflux that is necessary for cell survival and immune cell responses [34].

Viral Infections, Reactive Oxygen Species, and Selenium

Viral infections are associated with an increase in reactive oxygen species (ROS), which are known to have both favorable and unfavorable effects on the host’s cells and are important for the viral processes to maintain their infectious cycle [35,36]. ROS are a collection of molecules originating from molecular oxygen produced through redox reactions. Radical, having one free electron, and non-radical ROS may be formed by the partial reduction of oxygen [37,38].

Within the host cells, a balance between ROS production and ROS scavengers exists, where viral infections may create an unbalanced situation that develops into oxidative stress [36]. ROS scavengers and antioxidant systems that help to maintain redox homeostasis include catalase (CAT), superoxide dismutases (SODs), GPXs, TXNRDs, peroxidredoxin (PRDXs), and GSH. If oxidative stress remains unchecked, ROS may damage cellular proteins, lipids, and nucleic acids leading to adverse health effects and increasing the risk for several diseases [38,39].

Selenium plays a major role in redox regulation via its incorporation in the form of selenocysteine, into a family of proteins called selenoproteins [6]. Among these proteins, GPXs and TXNRDs play a critical role as antioxidants and confer protection against free radicals released by the immune response as a result of viral infection [8].

TXNRD defense involves the regulation of nuclear factor erythroid 2–related factor 2 (Nrf2) activation, which protects the cell against oxidative stress and inflammation [40], while GPX antioxidant defense involves the reduction of various hydroperoxides and oxidized antioxidants by catalyzing the conversion of GSH to glutathione disulfide [9]. Membrane integrity is also maintained through GPXs [41].

Studies have shown that inadequate Se intake affects GPX and TXNRD levels compromising cell-mediated immunity and humoral immunity linked to an increased inflammatory response by the production of ROS and redox control processes [40,42]. ROS production increases the expression of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, through the upregulation of NF-κβ activities [42].

Selenium acts as a crucial antioxidant through the modulation of ROS production by inflammatory signaling inhibiting the activation of NF-κβ cascade and suppressing the production of TNF-α and IL-6 [43]. Low Se levels decrease antioxidant activity thus decreasing free radical neutralization [44]. These studies suggest that Se deficiency alters immune response and viral infection by increasing oxidative stress and the rate of mutations in the viral genome, producing an increase in pathogenicity and damage to the host, as reported on influenza and coxsackie viruses [6].

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

The novel COVID-19 is caused by SARS-CoV-2, a single-stranded RNA coronavirus. The severity of the disease has been linked to aging and comorbidities such as hypertension, diabetes, obesity, cardiovascular disease, kidney disease, cancer, and pulmonary diseases [137,138]. Most of the people who test positive for COVID-19 develop mild or no symptoms, while others develop acute respiratory distress syndrome (ARDS), heart failure, blood clots, neurological complications, and elevated inflammatory response [137,139].

SARS-CoV-2 pathology has been associated with an increased immune response, leading to a release of cytokines and chemokines, also known as cytokine storm [140], as well as increased inflammatory markers such as D-dimer and ferritin [141,142]. This hyperactive inflammatory response may also bring about severe pathology in the brain [143].

SARS-CoV-2 may directly impact the central nervous system and enter the brain through various routes [144,145,146,147]. Increased systemic inflammation promoted by SARS-CoV-2 has the potential to disturb the blood-brain barrier and co-morbidities associated with severe cases of COVID-19 may enable the attack of the brain by SARS-CoV-2 [143,148].

It has been noted that there is a potential and developing relationship between Se levels and COVID-19 outcomes. Proposed mechanisms by which Se may act upon the SARS-CoV-2 virus based on previous research in RNA viruses include restoration of GPX and TXNRD thus reducing oxidative stress, reduction of viral-induced cell apoptosis, provision of Se for the host’s antioxidant needs, protection of endothelial cells, and reduced blood platelet aggregation [149,150].

COVID-19 is associated with a heightened level of oxidative stress and inflammation that are implicated in the pathogenesis of pulmonary disease [151]. GSH provides protection to the epithelial barrier within the lungs, and it has been suggested that improvement of GSH levels would be a strategy that may protect against inflammation and oxidant-related damage in the lungs [151].

A study conducted by Mahmoodpoor et al. [152] supplemented sodium selenite in patients with ARDS, often associated with severe cases of COVID-19, and found that it restored the antioxidant capability of the lungs, reduced inflammation, and improved respiratory mechanics. Lower total lymphocytes and CD4+ T, CD8+ T, B, and NK cells were found in COVID-19 patients and those with severe cases compared to mild cases of COVID-19 had lower lymphocyte subsets [153]. The function and differentiation of B and T cells may be affected by Se status [154]. Deficiency of Se in mice has been associated with lower T cell proliferation, while supplementation increased T cell activity and differentiation [155].

Clinical data investigating Se and COVID-19 are sparse; however, some reports from China and other countries globally have surfaced. In China, where there is a wide range of soil Se levels and thus a variation of Se daily intake, a linear association has been demonstrated between reported cure rates of COVID-19 and Se hair concentration data, dating from 2011 and older [156]. The same research group in China documented higher fatality risk in cities that had selenium-deficient levels in crops and topsoil compared to cities with non-deficient selenium levels in crops and topsoil [157].

Intake of Se varies worldwide, and China is known to be one of the most Se deficient countries in the world, with a wide range of levels that differs from lowest to highest in the world. COVID-19 fatality rate varies across different regions in China, suggesting that Se status may be related to COVID-19 outcomes [156,158]. In the city of Wuhan, where the SARS-CoV-2 virus was first discovered, and in other cities such as Suizhou and Xiaogan, low Se soil status was associated with the highest COVID-19 incidence [156].

In contrast, cities such as Enshi, Yichang, and Xiangyan, where high Se intake occurs, had the lowest COVID-19 incidence [156]. In contrast, in a retrospective study completed in Wuhan, China, with hospitalized COVID-19 patients, the severity of COVID-19 was associated with higher Se levels in urine [159]. The authors hypothesize that liver abnormalities due to the severity of the disease may have impacted the excess urinary Se found in severe COVID-19 patients [159].

Studies conducted in other parts of the world are showing similar relationships to those completed in China. In a study conducted in South Korea on hospitalized COVID-19 patients, 42% were found to be Se deficient and as the severity of disease increased, Se plasma levels decreased [160]. These patients also experienced additional nutritional deficiencies. COVID-19 patients compared to healthy controls in India, Iran and Russia had significantly lower plasma Se levels [161,162,163].

A greater rate of low plasma Se levels (<70 ng/mL) was found in COVID-19 patients (43%) compared to controls in India (20) [161]. Lung damage, as assessed by computer tomography, was inversely associated with Se levels in Russia [163].
COVID-19 patients may also experience increases in oxidative stress and increases in Se-related markers and lower Se levels have been documented in these patients. Moghaddam al. [164] observed an association between markers of Se status and COVID-19 outcomes from COVID-19 patients in Germany.

Serum Se and SELENOP concentrations were lower in COVID-19 patients compared to a reference European population. A comparison of patients that survived compared to those who died from COVID-19 showed that the deceased had a significantly greater deficiency of serum Se and SELENOP concentrations than those who survived. In addition, those who died had significantly lower serum Se, SELENOP levels, and GPX compared with patients who survived.

A study in Belgium using a convenience sample of patients hospitalized with severe COVID-19 pneumonia observed statistically lower GSH levels and higher GPX levels compared with reference intervals among other results showing elevated markers of oxidative stress and lower antioxidant status [165]. Recently, Polonikov [166] hypothesized that GSH deficiency plays a major role in augmenting SARS-CoV-2 oxidative damage, which leads to greater disease progression and mortality.

This viewpoint was based on data showing lower GSH and higher ROS levels in COVID-19 patients with mild disease and increasing severity that included higher viral load with GSH deficiency [166] and work completed by Hurwitz et al. [167] that demonstrated improvement in dyspnea with high dose oral and IV GSH in two patients with underlying conditions who tested positive for COVID-19.

These conclusions were based on very small samples and therefore require additional larger clinical studies to replicate the findings and eventual intervention studies. The evidence presented above suggests that Se availability contributes to resisting SARS-CoV-2 infection, corresponding with studies that show adequate levels of Se status maintains an appropriate immune response to viral infection [6,134,136].

There are no known published Se supplementation clinical trials in the context of COVID-19 at this time and one study is currently listed on clincaltrials.gov that will examine the efficacy of Se (selenious acid infusion also known as sodium selenite) for the treatment of moderately-ill, severely ill, and critically ill COVID-19 patients (Identifier: NCT04869579). Sodium selenite supplementation has been proposed for the prevention of COVID-19 infections and severe disease [149,168]. Sodium selenite is easily available, short-term toxicity is marginal and may cross the blood-brain barrier [149].

This chemical form may oxidize thiol groups located in the virus protein disulfide isomerase, which would interfere with its ability to infiltrate the cell membrane and produce an infection [168]. TXNRD activity increases quickly after supplementation with sodium selenite in cancer cell lines and critically ill patients [169,170] and has demonstrated reduced ROS production and viral-induced cell apoptosis in cell culture studies [171]. A common feature of COVID-19 is thrombotic complications and altered platelet function is believed to affect the sequelae of this infection [172].

Sodium selenite has also been shown to have an anti-aggregating effect through its reduction of thromboxane A2 formation, an important factor in blood platelet activation and formation [173]. The effectiveness of sodium selenite for the prevention and management of COVID-19 should be tested immediately as the COVID-19 pandemic continues to persist and threaten the health of individuals globally, thus necessitating rapidly accessible treatment strategies.

Since Se has pronounced therapeutic potential for the treatment of viral infections and other conditions such as cancer, Se nanomedicine has received a lot of attention. Se nanoparticles are known to have low toxicity with marked and selective cytotoxic effects with small quantities [174].

Additionally, Se nanoparticles have high effectiveness in the inhibition of oxidative damage [175,176,177]. Recently published data show that Se nanoparticles activate programmed cell death in target cancer tissue through calcium (Ca)2+ signaling pathways [178].

Immune cells also require calcium flux to generate oxidative stress [174]. Through chemical methods, Se nanoparticles may be produced with Se sources that include sodium selenite, selenious acid, and sodium selenosulfate [174]. Due to the developing relationship between Se and COVID-19, Se nanomedicine is being suggested as a tool in the fight against SARS-CoV-2 [179].

Currently, there are tremendous prospects of using nanomedicine in ARDS for the prevention, diagnosis, and treatment, which may have applicability for COVID-19 [180]. Jin et al. [181] discovered that an organic Se compound known as Ebselen, and a promising antioxidant drug, could inhibit SARS-CoV-2 by penetrating the cell membrane and displaying antiviral activity. Ebselen is known to have anti-inflammatory activity, mimic GPX activity, and should be considered for clinical studies [181,182].


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