Efficacy of Selenium for Controlling Infectious Diseases

Abstract

Selenium, an essential micronutrient for both animals and humans, has been documented to possess antimicrobial properties against a wide range of pathogenic microorganisms. One of the primary mechanisms by which selenium exerts its antimicrobial activity is through the generation of reactive oxygen species that can damage microbial cells. Besides its direct antimicrobial effects, selenium can enhance the immune response to infections, making it a potential tool in the prevention and treatment of infectious diseases. Given the growing threat of antibiotic resistance and the need for alternative therapeutic options, the antibacterial properties of selenium are of interest to the scientific community. This book chapter will summarize the current state of knowledge on the antibacterial properties of selenium, and its potential clinical applications as a therapeutic agent against infectious diseases. Further, the chapter explores the limitations and challenges associated with the use of selenium as an antibacterial agent.

1. Introduction

Selenium, a trace element discovered in 1817 by the Swedish chemist Jöns Jacob Berzelius, has since been demonstrated to be an indispensable micronutrient for human health. Although initially recognized for its practical value in preventing nutritional myopathies and vascular disorders in livestock, subsequent research revealed the numerous ways in which selenium contributes to overall human health and well-being.

Selenium has emerged as an essential component of several selenoproteins that play a crucial role in various physiological processes in humans. These processes include antioxidant defense, immune function, thyroid hormone metabolism, and redox homeostasis. The importance of selenium in human health became apparent when researchers discovered its role in glutathione peroxidase (GPx) in 1973, as well as its ability to prevent liver necrosis in vitamin E-deficient rats. This enzyme, which contains selenium as an integral part of its structure, is a potent antioxidant that neutralizes harmful reactive oxygen species (ROS) and protects cells from oxidative damage.

Selenium’s role in human health received increased attention with the observation that selenium deficiency could lead to serious diseases such as Keshan disease, an endemic cardiomyopathy affecting people in selenium-deficient regions of China [1]. This discovery prompted further investigation into the geographical distribution of selenium intake and its impact on public health. Subsequent research has established that selenium deficiency is associated with a higher risk of certain cancers, impaired immune function, and cognitive decline. On the other hand, selenium toxicity, although rare, can occur when excessive amounts of the element are consumed, leading to conditions such as selenosis, which is characterized by symptoms such as hair loss, brittle nails, and gastrointestinal disturbances [2].

In recent years, the antimicrobial properties of selenium and its potential applications in combating pathogens of public health significance have become an area of growing interest. Recent advancements in nanotechnology have led to the development of selenium nanoparticles (SeNPs), which exhibit enhanced antimicrobial properties due to their increased surface area and unique physiochemical properties. SeNPs have been shown to exert direct antimicrobial effects, disrupt biofilms, and to improve host immune responses, making them a potential therapeutic agent against many pathogens.

Despite the growing body of evidence supporting selenium’s antimicrobial properties, our understanding of its multifaceted functions in the human body remains incomplete. In this chapter, we will delve into the intricate mechanisms through which selenium exerts its immunomodulatory, antibacterial, and antiviral effects, and explore the potential applications of selenium in medicine and disease prevention. By providing a comprehensive understanding of the potential benefits of selenium in the context of human health and disease prevention, this chapter will shed light on its pivotal role in combating pathogens of public health significance.

2. Enhancement of immune response and combating pathogens with selenium and selenium nanoparticles

Selenium is renowned for its capacity to enhance immune responses against infections through multiple mechanisms. It can increase the number of T cells, improve the proliferative responses of lymphocytes to mitogens, stimulate the secretion of the cytokine IL-2, and enhance the activity of natural killer (NK) cells. These combined effects contribute to the strengthening of immune defences against various pathogens [3]. Selenium’s ability to boost the immune system and reduce inflammation can be mainly attributed to its antioxidant properties where its primary role is to regulate the function of GPx. Gpx in turn, decreases the levels of hydrogen peroxide and phospholipid hydroperoxides, preventing the generation of free radicals and ROS [4]. It also decreases hydroperoxide intermediates in the metabolic pathway of arachidonic acid, consequently reducing the production of inflammatory prostaglandins and leukotrienes [5].

The main mechanism of action for selenium involves its interaction with selenoproteins, which include antioxidant enzymes like GPxs and thioredoxin reductases (TrxRs). Selenoproteins are composed of the amino acid selenocysteine (Sec), which is integrated into the protein structure during translation. This occurs after the conversion of O-phosphoseryl-transfer RNA (O-phosphoseryl-tRNA) [Ser]Sec into selenocysteyl tRNA[Ser]Sec [6]. Selenium deficiency as well as small changes in the expression and genetic variations of certain selenoproteins have been linked to cancer and immune dysfunction. Among the 25 genes encoding human selenoproteins, immune cells express most of them pointing towards its immune potential. Notably, the GPx isoenzymes GPx1 and GPx4 exhibit the highest expression levels in both T lymphocytes and macrophages [7]. Studies have demonstrated that selenite supplementation can enhance the production of 15-deoxy-D(12,14)-prostaglandin J2, an anti-inflammatory compound derived from arachidonic acid, by upregulating prostaglandin D2 synthase. Additionally, selenite has been found to reduce the production of the proinflammatory prostaglandin E2 (PGE2) in murine macrophages [8]. Selenium supplementation in patients with low selenium status activated the proinflammatory cellular (Th1-type) immune response against pathogens, while preventing excessive immune system activation and tissue damage by favoring macrophage differentiation to the more anti-inflammatory M2 phenotype [9].

Research has indicated that the addition of selenium to poultry diets can result in elevated expression of interferon and ISG (interferon-stimulated genes) in lymphoid tissue cells playing a crucial role in enhancing the antiviral responses of these cells [5]. Additionally, selenium enhances the activity of various immune cells such as neutrophils, macrophages, NK cells, and T lymphocytes. It also promotes the production of antibodies and regulates the production of cytokines, including an increase in IL-2 and a reduction in TNF and IL-8. Moreover, selenium has preventive effects against inflammatory diseases by reducing the activation of Nuclear Factor kappa B (NF-κB) and the production of pro-inflammatory cytokines. Selenium exhibits cytotoxic effects and has the potential to induce apoptosis in tumor cells. Selenium also offers protection against UV radiation, reduces viral virulence, and contributes to the prevention of atherosclerosis and cardiovascular diseases [9].

Selenium nanoparticles (SeNPs) have also shown the capability to modulate autophagy in different cancer cells, a process commonly associated with the induction of cancer cell death or apoptosis. SeNPs lead to the formation of autophagosomes and enhance autophagy by regulating specific proteins involved in autophagy, such as Beclin-1, LC3-II, and p62 [10]. Importantly, autophagy plays a role in regulating immune functions that can impact the infection and survival of pathogens within host cells. Moreover, selenium nanoparticles have demonstrated significant immunomodulatory effects by influencing various immune cells and modulating essential signalling pathways associated with the immune response. With the emergence of chimeric antigen receptor T-cell (CAR-T) therapy, immunotherapy has become a promising new treatment for malignant tumors [11].

Studies have demonstrated that the inclusion of dietary chitosan-selenium nanoparticles (CTS-Se NPs) can improve the immune response and disease resistance in zebrafish when exposed to the bacterium Aeromonas hydrophila [12]. Following treatment with CTS-Se NPs, zebrafish splenocytes exhibited higher proliferation when stimulated with lipopolysaccharide (LPS) and concanavalin A (ConA). The immune response of splenocytes against ConA was found to be associated with the up-regulation in IL-2 and IL-12 production. Moreover, SeNPs can promote host antibacterial immunity by inducing host cell apoptosis, autophagy, and M1 anti-bacterial polarization, which significantly enhances the intracellular Mycobacterium tuberculosis killing efficiency [13].

3. Antibacterial activity of selenium and selenium nanoparticles

Selenium has recently gained attention for its potential antibacterial properties. Research has demonstrated its ability to interfere with the growth and metabolism of various bacterial species, making it a promising candidate for the prevention and treatment of bacterial infections. Selenium has been shown to inhibit the growth of several pathogenic bacteria, including Staphylococcus aureus, Escherichia coli, and Helicobacter pylori. Furthermore, selenium can enhance the antibacterial effects of conventional antibiotics, potentially reducing antibiotic resistance. This section delves into the mechanisms underlying selenium’s antibacterial properties and its prospective applications in the prevention and treatment of bacterial infections.

In both eukaryotes and prokaryotes, selenium plays essential roles in diverse biological processes, including redox homeostasis, thyroid hormone metabolism, and immune function. Prokaryotes express a wide range of selenoproteins, with approximately 20% of sequenced prokaryotic genomes encoding at least one trait for selenium utilization. These selenoproteins participate in multiple selenium-dependent enzymes (such as formate dehydrogenase in Methanococcus jannaschii and glycine reductase in Clostridioides difficile) and may confer increased fitness to prokaryotes in the presence of selenium, similar to the benefits observed in humans and other mammals [14].

This intricate interplay between host and pathogen during infection poses a challenge for the mammalian host, as both parties compete for the limited selenium resources. Despite its importance, limited information is available regarding the role of selenium in bacterial physiology, virulence, and overall pathogenesis. The literature documenting the antimicrobial activity of selenium toward various pathogenic microorganisms is summarized below.

3.1 Staphylococcus aureus

Staphylococcus aureus is an opportunistic Gram-positive bacterium that can cause illnesses ranging from mild skin infections to more severe illnesses such as necrotizing pneumonia and bacteremia. Besides this, there is an increasing concern for antibiotic resistance among S. aureus including methicillin-resistant strains. As a result, there is a growing interest in exploring selenium as a potential therapeutic agent for controlling S. aureus infections [15].

The immune system’s response to S. aureus infection involves the activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, which play central roles in inflammation and the production of pro-inflammatory cytokines, including TNF-a, IL-1B, and IL-6 [16]. S. aureus has developed various strategies to evade the host’s immune response, such as producing virulence factors to resist the mitochondrial agents generated by phagocytosis and competing with inducible nitric oxide synthase (iNOS) for the shared substrate arginine. Selenium, as an antioxidant and a vital component for optimal immune cell functioning, may aid in the host response to S. aureus infection.

Selenium-supplemented macrophages have been shown to produce reduced amounts of nitric oxide (NO) while increasing ROS production, particularly hydrogen peroxide. This supplementation also decreases bacterial arginase activity, limiting the bacterium’s tolerance to oxidative stress. Furthermore, selenium enhances phagocytosis and increases the bactericidal capacity in a dose-dependent manner [15]. In the context of S. aureus infection, selenium supplementation has been found to decrease inflammatory cytokine gene expression and protein levels, such as TNF-a, IL-1b, and IL-6. Selenium inhibits the activation of both NF-κb and MAPK signaling pathways by suppressing the phosphorylation of IkBa, p65, Erk, jnk, and p38, thereby attenuating the overall inflammatory response [16].

Selenium has also been demonstrated to possess an immunoregulatory function on inflammation in mammary epithelial cells and glandular tissue during S. aureus-induced mastitis [17] and selenium supplementation was shown to decrease mastitis incidence in dairy cattle [18]. Selenium deficiency results in increased pro-inflammatory cytokine levels, while supplementation promotes anti-inflammatory cytokine expression and inhibits NF-κB activation [19]. Additionally, selenium inhibits S. aureus infection of the uterus and reduces the activation of toll-like receptor-2 (TLR-2) inflammatory signaling, decreasing caspase activity [20].

S. aureus is known to produce biofilms, which contribute to antibiotic resistance and chronic infections. The use of selenium nanoparticles (SeNPs) has shown promise in addressing this challenge. SeNPs have demonstrated significant inhibitory effects on S. aureus growth during the early stages of infection, potentially preventing biofilm formation [21]. Furthermore, SeNPs exhibit both anti-adherence and anti-microcolony formation properties against S. aureus biofilms indicating their potential to disrupt biofilm formation [22].

A practical application of SeNPs has been observed in coating titanium implants. These coatings have demonstrated potent antimicrobial activity against drug-resistant strains, such as methicillin-resistant S. aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis. The SeNP-coated implants effectively inhibited biofilm formation and reduced bacterial viability [21]. This suggests the potential use of selenium nanoparticle coatings as an effective anti-infective barrier for orthopedic medical devices, offering a novel approach to combating biofilm-associated infections.

Diabetic foot wounds, which are often infected by antibiotic-resistant bacteria such as MRSA, require alternative antimicrobial drugs. A hybrid nanostructure comprising selenium, chitosan, and mupirocin has demonstrated significant antimicrobial activity against MRSA. This system played a crucial role in wound healing by reducing the minimum inhibitory concentrations (MIC) of mupirocin, and promoting wound contraction, angiogenesis, fibroblastosis, collagen production, and growth of hair follicle and epidermis [23].

Selenium holds promise as a therapeutic agent for controlling S. aureus infection, with research highlighting its potential in enhancing the immune response, preventing biofilm formation, and promoting wound healing. Additional studies are needed to ascertain the ideal dosage and explore its applications in clinical settings.

3.2 Escherichia coli

Escherichia coli is a Gram-negative bacterium that typically resides in the lower intestinal tract of humans and animals. Though the majority of E. coli are harmless, some can cause severe infections, such as gastrointestinal illness, urinary tract infections, and meningitis. The emergence of antibiotic-resistant strains of E. coli has led to a growing need for alternative treatments.

Selenium deficiency, especially in conjunction with vitamin E deficiency, has been found to exacerbate the pathology of gastrointestinal tract diseases caused by pathogenic E. coli such as those caused by enteropathogenic E. coli (EPEC) [24]. Deficiency in these nutrients leads to heightened oxidative stress, which in turn causes increased pro-inflammatory signaling and tissue damage. On the other hand, selenium-enriched probiotics have demonstrated protective effects against pathogenic E. coli in the gut, enhancing antioxidant performance, inhibiting pathogenic bacterial colonization, and bolstering immunity [25].

Selenium-enriched probiotics have been found to outperform sodium selenite in raising serum selenium levels, most likely due to the improved absorption of organic selenium compounds over inorganic ones [14]. These probiotics adhere to the intestine, effectively preventing pathogenic bacteria such as E. coli from interacting with potential binding sites. This emphasizes the capacity of selenium-enriched probiotics to support gut health by improving antioxidant performance, preventing pathogenic bacterial colonization, enhancing immunity, and reducing enteric illnesses.

Selenium supplementation has been reported to aid in the resolution of chronic bacterial prostatitis (CBP) caused by E. coli, especially when used in conjunction with antibiotics [26]. The current primary treatment against CBP involves the use of antibiotics, which necessitate small molecular weight and fat-soluble properties to facilitate diffusion across the prostate epithelial membrane. Combining selenium with the antibiotic ciprofloxacin resulted in a significant reduction of E. coli in the CBP model and a considerable decrease in inflammatory cell infiltration within the prostate tissue.

Selenium has also exhibited inhibitory effects on biofilm formation in uropathogenic E. coli (UPEC), which is responsible for 80% of urinary tract infections. Selenium reduces exopolysaccharide synthesis and downregulates biofilm-associated genes (fimA, fimH, papG, focA, sfaS) [27]. Moreover, it has proven effective in deactivating pre-established UPEC biofilms on urinary catheters.

In the context of enterohemorrhagic E. coli O157:H7, a foodborne pathogen, selenium has been shown to inhibit biofilm formation by reducing attachment, decreasing EPS production, and downregulating genes involved in biofilm production [28]. Additionally, selenium supplementation lowered extracellular and intracellular verotoxin levels, downregulated verotoxin genes, and reduced Gb3 receptor synthesis (receptor for verotoxin) in lymphoma cells by downregulating the LacCer synthase gene involved in Gb3 synthesis [29].

Although sodium selenite does not directly exhibit antibacterial properties against E. coli and other bacteria (Bacillus subtilis, Bacillus mycoides, and Pseudomonas spp.), it has been found to enhance the inhibitory effects of ampicillin and streptomycin on these bacterial growth [30]. This suggests that selenium supplementation may function as an adjuvant, complementing conventional antibiotic therapy in the treatment of E. coli infections.

3.3 Helicobacter pylori

Helicobacter pylori is a Gram-negative, microaerophilic, helix-shaped bacterium that colonizes the gastric mucous layer or adheres to the epithelial lining of the stomach [31]. Present in approximately 50% of the human population worldwide, H. pylori is responsible for causing 90% of duodenal ulcers and 80% of gastric ulcers [9], with infected individuals facing an increased risk of developing gastric cancer and mucosal-associated-lymphoid type lymphoma [31].

Currently, the treatment for H. pylori infection in humans involves a combination of proton pump inhibitors, amoxicillin, and clarithromycin [31]. However, H. pylori has shown to develop resistance to clarithromycin, leading to decreased eradication rates.

During H. pylori infection, micronutrient homeostasis, including that of selenium, is frequently disrupted, with equilibrium typically restored upon successful eradication of the pathogen [32]. Interestingly, whole plasma selenium level remains consistent between patients with or without H. pylori induced inflammation, and antral mucosa of individuals with H. Pylori-associated gastritis exhibits higher levels of selenium [33, 34, 35]. Moreover, increased inflammation scores of the antral mucosa correlate with elevated tissue selenium concentrations [33].

This increase in selenium concentration at the infected mucosa may be a protective response, where selenium acts as an antioxidant to prevent further damage caused by ROS or mediated the resolution of inflammation. This is supported by the decrease in gastric tissue selenium observed in patients after successful eradication of H. pylori [33]. A combination of antioxidants, including vitamins A, C, and E, and selenium, has been shown to protect against H. pylori infection and reduce gastritis severity in guinea pigs, highlighting the potential benefits of dietary antioxidant supplementation in the prevention and management of H. pylori-associated diseases [36].

It is essential to note that selenium deficiency has been identified as a risk factor for the conversion of precancerous gastric lesions into carcinomas [33]. The decline in selenium may be due to long-lasting mucosal inflammation, which results in an altered gastric microenvironment leading to gastric carcinogenesis. These findings suggest that selenium supplementation could aid in preventing the onset of gastric carcinogenesis in chronically infected individuals and reduce mortality in those who already have gastric ulcer [37]. Furthermore, one study indicates a correlation between selenium status and location of gastric cancer [38]. Additional research is needed to investigate why selenium levels drop before carcinogenesis and the mechanisms behind this occurrence.

3.4 Vibrio species

Selenium has demonstrated potential in combating infections caused by Vibrio species, such as Vibrio cholerae and V. parahaemolyticus. These pathogenic bacteria cause toxin-mediated diarrhea and seafood-related gastroenteritis in humans, respectively, and can lead to severe dehydration and even death in untreated patients. Innovative strategies to control and prevent such infections are necessary for enhanced public health.

Selenium has been shown to reduce V. cholerae’s motility, intestinal cell attachment, and cholera toxin production. The reduction in motility, an essential step in the pathogenesis of V. cholerae, may be due to alterations in membrane integrity that affect flagellar structure. These findings suggest that selenium supplementation can benefit the host by enhancing their immune response, while simultaneously decreasing the virulence of the bacterial pathogen [39].

Biogenic selenium nanoparticles stabilized using seaweed have exhibited significant antibacterial activity against V. parahaemolyticus. Scanning electron microscopy analysis revealed that the nanoparticles interact with the bacterium, attaching to the cell membrane and causing non-viability [40]. Similarly, selenium nanoparticles synthesized from marine macroalgae have demonstrated antimicrobial activity against pathogenic V. harveyi and V. parahaemolyticus [41]. This finding suggests the potential applicability of these nanoparticles in combating a broader range of Vibrio species in aquaculture.

3.5 Clostridioides difficile

Clostridioides difficile is a pathogenic bacterium causing toxin-mediated enteric disease in humans, mainly affecting hospital inpatients and the elderly undergoing prolonged antibiotic therapy. The rise of hypervirulent strains has resulted in C. difficile being listed as one of three urgent threats to human health. Although antibiotics are the drug of choice for treating C. difficile infections, the emergence of antibiotic resistance has led to the investigation of alternative treatments. The use of sodium selenite as an alternative therapeutic agent was shown to reduce the virulence of C. difficile by reducing exotoxin production without affecting the growth of beneficial bacteria commonly found in the human gastrointestinal tract. Furthermore, sodium selenite significantly increased the sensitivity of C. difficile to ciprofloxacin [42].

3.6 Acinetobacter baumannii

Acinetobacter baumannii is a multidrug-resistant pathogen that causes wound infections in humans. Due to its ability to form biofilms and colonize epithelial cells, A. baumannii infections can be difficult to treat. A study exploring the potential of selenium in inhibiting A. baumannii’s ability to form biofilms and colonize human skin keratinocytes was found to reduce bacterial adhesion and invasion of human skin keratinocytes, disrupt biofilm architecture, and downregulate genes associated with biofilm production [43].

3.7 Selenium nanoparticles for bacterial infections

Selenium nanoparticles (SeNPs) have garnered attention for their unique physicochemical properties, which include size, surface charge, and concentration, all of which influence their antimicrobial activity. The differential antimicrobial effects of SeNP on Gram-positive and Gram-negative bacteria, as well as fungi like Candida species, have been explored in several studies. For example, SeNPs synthesized by Providencia vermicola BGRW exhibited a strong inhibitory effect on the growth of several Gram-positive pathogens (such as S. aureus, B. cereus, methicillin-resistant S. aureus, and Streptococcus agalactiae) and E. coli, but most Gram-negative bacteria and Candida albicans were not inhibited [44].

The surface charge of SeNPs, which can be either positive or negative depending on the synthesis method, affects their interaction with bacterial cells. Studies have shown that negatively charged nanoparticles exhibit higher antimicrobial activity against Gram-positive bacteria due to electrostatic attraction between the negatively charged nanoparticles and the positively charged bacterial cell surface [14]. On the other hand, negatively charged SeNPs do not exhibit the same effect on Gram-negative bacteria, as the small size of penetration channels in their cell walls and the insufficient negatively charged regions on the cell wall hinder the attachment of positively charged SeNPs.

SeNPs also exhibit potential as an antimicrobial agent in combination with conventional antibiotics. By increasing the bioavailability of these agents and reducing the likelihood of antibiotic resistance, SeNPs can enhance the effectiveness of existing treatments. For instance, Menon et al. [45] demonstrated that Klebsiella sp. was the most susceptible to SeNP administration at a concentration of 100 μg/ml, with Serratia sp. and S. aureus also exhibiting significant growth reduction. SeNPs can be produced by lactic acid bacteria at ambient temperatures and pressures, providing a cost-effective and environmentally friendly alternative to chemically based methods [46].

3.7.1 Selenium nanoparticles against foodborne pathogens

The biosynthesized SeNP from Bacillus licheniformis has been shown to effectively control growth and biofilm formation of foodborne pathogens such as B. cereus, Enterococcus faecalis, E. coli O157 H7, S. aureus, Salmonella Typhimurium, and S. enteritidis. Although they did not completely remove established biofilms, a concentration of 75 mg/ml showed a slight effect, and SeNPs demonstrated no toxicity on Artemia larvae, making them a promising agent for preventing biofilm formation by foodborne pathogens [47].

3.7.2 Selenium nanoparticles against Pseudomonas aeruginosa

The antibacterial activity of SeNP synthesized by Stenotrophomonas maltophilia and Bacillus mycoides was assessed against clinical isolates of Pseudomonas aeruginosa. These SeNPs demonstrated inhibitory effects on bacterial growth at concentrations ranging from 8 to 512 mg/ml. Conversely, the SeNP displayed no inhibitory activity against Candida albicans and Candida parapsilosis species [48]. These findings suggest that antibacterial activity of SeNP may be bacterium specific. Consequently, researchers have sought to optimize the physicochemical properties of SeNP, such as stabilization and interaction with biological molecules to broaden their spectrum of antimicrobial activity.

3.8 Selenium interactions with antimicrobials

SeNPs have demonstrated promising synergistic activity when combined with other antimicrobials. In a study that explored the potential synergistic effects, SeNPS were generated using a simple wet chemical method and combined with a set concentration of lysozyme, creating a nanohybrid system incorporating both SeNPs and lysozyme. Antibacterial tests were conducted on S. aureus and E. coli, revealing that SeNPs played a crucial role in inhibiting bacterial growth at very low protein concentrations. Furthermore, individual nanoparticles effectively suppressed bacterial growth even in the presence of high lysozyme concentrations when used in the modest amounts [49].

Huang et al. developed a synergistic nanocomposite by conjugating quercetin and acetylcholine to the surface of SeNPs, which are synthesized by chemically reducing Na2SeO3 [50]. According to their findings, the nanoparticles interacted with the bacterial cell wall, causing permanent damage to the membrane, and exhibiting remarkable synergistic antibacterial activity against MRSA at low doses. The results suggest that the synergistic effects of quercetin and acetylcholine increase the antibacterial activity of SeNPs [50].

Cihalova et al. reported that SeNPs possess potent inhibitory action when combined with conventional antibiotics. Using an impedance method, they observed a greater disruption of biofilms after applying antibiotic complexes containing SeNPs compared to those treated with antibiotics alone. In comparison with bacteria without antibacterial compounds, the nanoparticles inhibited the formation of MRSA biofilms by up to 94% ± 4%, while drugs without SeNPs only suppress MRSA by up to 16% ± 2% [51]. This evidence highlights the potential for SeNPs to enhance the efficacy of antimicrobial treatments through synergistic interactions with other antimicrobials.

4. Antiviral activity of selenium and selenium nanoparticles

Beyond its involvement in bacterial infections, selenium has also been implicated in viral infections. Studies have indicated that selenium deficiency can exacerbate the pathogenicity of certain viruses, while adequate selenium levels contribute to improved immune responses and viral clearance. Selenium is vital in defending the host system against viral infections in various infectious diseases. Nutritional deficiencies in selenium can affect both the pathogenicity of a virus and the immune system’s response [52]. Selenium compounds, such as selenite, can inhibit viral invasion of healthy cells and reduce their infectiousness [53]. Moreover, selenium and vitamin E supplements have shown to increase resistance to respiratory viral infections [3].

4.1 SARS-CoV-2

The COVID-19 pandemic, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), emerged in 2019 and has globally affected about 530 million people, causing 6.3 million deaths [54]. Selenium may protect the host due to its critical role as a cofactor for enzymes that work with vitamin E to reduce the generation of ROS, which can cause oxidative damage in both pathogen and host cells [55]. The main SARS-CoV-2 protease interacts with glutathione peroxidase1 (GPX1), a crucial selenium-dependent enzyme responsible for viral replication [56]. Notably, the GPX1 mimic synthetic selenium compound ebselen is a potent inhibitor of SARS-CoV-2 virus main protease enzyme [57].

Sodium selenite can oxidize the thiol groups on the surface of the coronavirus protein disulfide isomerase, preventing it from penetrating healthy cell membranes. Wang et al. demonstrated the potential of SeNPs for COVID-19 diagnosis using a lateral flow immunoassay kit based on SeNPs-modified SARS-CoV-2 nucleoprotein, which detected anti-SARS-CoV-2 IgM and IgG in human serum within 10 minutes with the naked eye [58].

4.2 Human immunodeficiency virus

Human immunodeficiency virus (HIV) is an RNA virus in the Lentivirus genus that causes acquired immunodeficiency syndrome (AIDS), leading to a compromised immune system by infecting immune cells. HIV currently affects over 37 million individuals and causes 1.5 million annual deaths [59]. Selenium has been shown to suppress HIV in vitro due to its antioxidant properties as a component of GPx and other selenoproteins. Many studies have reported low serum selenium levels in HIV-positive individuals, and serum selenium levels decrease as the disease progresses. Several cohort studies have established a link between selenium deficiency and the development of AIDS. Although some randomized controlled trials have shown that selenium supplementation can improve CD4+ cell counts and reduce hospitalizations and diarrheal morbidity, additional follow-up studies are needed to confirm this finding [60].

4.3 Influenza virus

Influenza virus affects the respiratory tract, and acute pneumonia is diagnosed in 30–40% of hospitalized individuals with laboratory-confirmed influenza. Influenza A is the most common viral cause of acute respiratory distress syndrome (ARDS) in adults [61]. Selenium therapy has been shown to modify the response to the influenza vaccination in older adults, which was associated with elevated IFN-γ levels following vaccination [62, 63]. Li et al. developed oseltamivir adorned SeNPs to treat the H1N1 virus. These compounds significantly hindered the H1N1 influenza virus’s ability to bind to host cells by preventing the activities of hemagglutinin and neuraminidase [13, 64]. SeNPs have demonstrated potential in combating the H1N1 influenza virus by blocking the ROS-mediated AKT and p53 signaling pathways, thereby preventing apoptosis, DNA fragmentation, chromatin condensation, and ultimately, cell death [28, 65]. Moreover, SeNPs can prevent cellular and lung tissue damage caused by the H1N1 virus [66]. Studies in broiler chickens revealed that while hexanic extracts of fig and olive fruit, along with nano-selenium, induced some immunity against the H9N2 avian influenza virus, they were unable to prevent anamnestic reactions or infections [67]. Research by Shojadoost et al. indicated that selenium supplementation enhances the immunity provided by vaccines, as shown by increased antibody levels (IgM and IgY) and reduced virus shedding in chickens treated with organic and inorganic selenium [68]. In mice, a ruthenium-selenium metal complex exhibited antiviral mechanisms by inhibiting viral assembly and replication, controlling virus-mediated apoptosis, and reducing lung tissue inflammation [69].

4.4 Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS), a common cause of respiratory failure in critically ill patients, is characterized by noncardiogenic pulmonary edema, hypoxemia, and mechanical ventilation requirements [70]. A case study investigated the impact of sodium selenite on ARDS and found that patients treated with it for 10 days experienced reduced airway resistance, improved lung compliance, increased fraction of inspired oxygen (FiO2), higher arterial oxygen pressure (PaO2), shorter hospital stays, and lower mortality rates. Selenium supplementation was found to restore lung antioxidant capacity, regulate inflammatory responses via interleukin (IL)-1 and IL-6 levels, and significantly enhance respiratory mechanics [71, 72].

4.5 Hepatitis virus

Viral hepatitis, which causes over 1.3 million deaths annually worldwide, is a major global health concern [73]. Although current anti-HIV drugs help control the epidemic, side effects and drug resistance call for safer and more effective treatment options. Sodium selenite has been found to inhibit Hepatitis B virus (HBV) protein expression, transcription, and genome replication in hepatoma cell cultures in a dose-dependent manner [13, 74]. By administering SeNPs and the hepatitis B antigen vaccination, Mahdavi et al. devised a method that could increase IFN-g levels, stimulate a Th1 response, and thus improve vaccine efficacy by activating the immune system toward a Th1 state [75].

4.6 Enterovirus

Enterovirus 71 (EV71) is the primary pathogen responsible for severe cases of hand, foot, and mouth disease (HFMD), for which there is currently no effective treatment [76]. Oseltamivir, a potent antiviral drug, was loaded onto SeNPs to enhance its antiviral activity against EV71. The functionalized SeNPs improved oseltamivir’s efficacy by inhibiting EV71 growth, preventing cell death, and reducing caspase-3 activity and ROS generation [76]. Additionally, SeNPs were used to load small interfering RNA (siRNA) targeting the EV71 Vp1 gene, with polyethylenimine (PEI) decorating the surface (Se@PEI@siRNA). In nerve cell line, Se@PEI@siRNA demonstrated high interference efficiency and protected cells from infection [77].

5. Antifungal activity of selenium and selenium nanoparticles

Selenium has emerged as a promising agent in mitigating the harmful effects of mycotoxins such as aflatoxin B1 (AFB1) and ochratoxin A (OTA), which pose significant health risks and economic losses due to their prevalence in foods. Further, SeNPs have recently gained interest for their superior antifungal properties and ability to inhibit the growth of multidrug-resistant fungus, offering potential strategies against mycotoxin-induced health issues.

AFB1 is a potent mycotoxin produced by certain strains of Aspergillus fungi (such as Aspergillus flavus and Aspergillus parasiticus), and is a prevalent contaminant in food, contributing to health issues in humans. Chronic exposure to AFB1 has been associated with immune toxicity, carcinogenicity, genotoxicity, hepatotoxicity, and reproductive disorders. AFB1 undergoes bioactivation in the liver to a highly reactive form exo-AFB1–8,9-epoxide (AFBO) that can cause DNA damage. Selenium-fortified yogurt has been shown to mitigate the harmful effects of aflatoxins in mice, such as weight loss and reduced food intake, by enhancing aflatoxin detoxification pathways and preventing AFB1-DNA adduct formation [78]. AFB1 can also trigger oxidative stress by generating ROS, potentially necessitating cytochromeP450 (CYP450) activation. Dietary selenium was shown to mitigate AFB1-induced liver damage in chickens by inhibiting CYP450 activation of AFB1 and enhancing antioxidant responses through selenoprotein gene upregulation [79]. AFB1 has also been reported to impair immune function, increasing susceptibility to infectious diseases. However, selenium supplementation, especially in the form of organic selenium, selenomethionine (SeMet), has demonstrated promising results in ameliorating AFB1-induced immune toxicity. The protective effects of SeMet were largely attributed to its ability to boost the expression of GPx1 and selenoprotein S, key element in antioxidant defense [80]. Selenium has also been the subject of extensive research due to its potential role in activating testosterone synthesis. Research has demonstrated the protective effects of selenium against AFB1-induced testicular toxicity. Specifically, selenium was found to improve testes index, sperm functional parameters (including concentration, malformation, and motility), and serum testosterone levels in AFB1-exposed mice. These findings suggest that selenium can effectively mitigate the oxidative stress and impaired testosterone synthesis induced by AFB1 exposure [81].

Kashin-Beck disease (KBD) characterized by severe osteoarthritis has been associated with low environmental selenium and the involvement of mycotoxins. A study conducted by Hong et al. has shown that selenium influences the growth of Fusarium strains and decreases chondrocyte injury indicators when chondrocytes are exposed to extracts from these fungal cultures. These findings suggest a link among environmental selenium levels, fungal metabolite production, and chondrocyte damage, which warrants further exploration [82].

Ochratoxin A, a mycotoxin produced by Penicillium and Aspergillus molds, poses significant health risks due to its widespread presence in crops and its ability to cause kidney and liver lesions, immune dysfunction, and genotoxicity in humans and animals. The exact mechanism of OTA’s toxicity, which has been linked to oxidative stress and cytotoxicity, remains under investigation [83, 84]. However, recent research suggests that selenium may counteract OTA’s cytotoxicity and oxidative stress damage. Various studies have shown that selenium can enhance cell survival after OTA exposure, activate the antioxidant response, and reduce oxidative stress and apoptosis in OTA-induced kidney injury [85]. Both SeMet and sodium selenite have demonstrated protective effects, possible through upregulation of antioxidant enzyme expression and the downregulation of apoptosis-related factors [86]. In combination with zinc, selenium was found to alleviate ochratoxin A-induced fibrosis in human kidney cells by blocking ROS dependent autophagy offering a new perspective on nutritional interventions against mycotoxin-induced health issues [87].

More recently, the role of biosynthesized selenium nanoparticles has gained attention due to their enhanced antifungal properties. Studies have shown that SeNP, biosynthesized using plant extracts or Aspergillus oryzae fermented lupin extract, can effectively inhibit the growth of multidrug-resistant bacteria and pathogenic fungi [88]. These nanoparticles have also demonstrated an effect on the expression of CYP51A and HSP90 antifungal resistance genes in Ammophilus fumigatus and A. flavus [89]. In Candida albicans isolates, biogenic SeNP was found to reduce the expression of ERG11 and CDR1 genes that are associated with azole resistance [90]. Furthermore, when compared to gold and silver nanoparticles, SeNPs exhibited superior antifungal properties against amphotericin B-resistant Candida glabrata clinical isolates [91]. Furthermore, the capacity of biogenic SeNPs to disrupt biofilms, particularly those formed by C. albicans, a primary causative agent of hospital-related infections stemming from biofilms on medical devices, has also been effectively demonstrated [92] without being cytotoxic to human embryonic kidney cells, thereby highlighting their potential as safe and efficacious agent in combating such infections.

To summarize, selenium, whether in its organic form or as biosynthesized nanoparticles, displays significant antifungal properties. By mitigating mycotoxin-induced toxicity and inhibiting the growth of various fungal species, selenium serves as a potential candidate for the development of novel antifungal strategies.

6. Limitations and toxicity of selenium

While selenium is an essential micronutrient with numerous health benefits, its toxicity and potential adverse effects must be considered. The toxicity of selenium depends on its chemical form, with organic selenium compounds generally being less harmful than their inorganic counterparts. However, the lethal dose (LD50) values can vary significantly based on the duration of exposure, the model employed, and the blood levels reached [93].

Recent studies have shown that intravenous administration of sodium selenite at a dose of 500 μg/day is non-toxic [94], and even relatively high dosages (up to 2000 μg/day) were well tolerated in individuals with peritonitis [95]. Nevertheless, excessively high selenium blood levels (>1 mg/L) can lead to selenosis, a condition characterized by gastrointestinal disturbances, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage [96]. The sodium selenite LD50 dose for rats is 4100 μg/kg body weight, which is 100 times higher than the dose typically used in humans [53]. In human serum, selenium concentrations range from 400 to 3000 μg/L, with levels above 1400 μg/L being non-toxic [93]. It is generally believed, though not definitively proven, that hazardous levels of selenite begin at 600 μg/day [53].

Given the potential toxicity of selenium at high doses, it is crucial to control the therapeutic dose. Plant-based nanoparticles may help mitigate the harmful effects of selenium, as they have been found to be less toxic than inorganic selenium [97]. Various physical and chemical methods have been employed to produce SeNPs, involving the use of different chemical compounds and physical processes. However, the high cost of these technologies and the potential contamination of nanoparticles with harmful chemical residues limit SeNPs therapeutic application in the pharmaceutical and medical industries [97]. As research into selenium’s antimicrobial properties continues, it is essential to maintain a balance between its therapeutic benefits and potential adverse effects.

6.1 Microbial resistance to selenium

Although selenium has demonstrated antimicrobial properties, the potential for microbial resistance to selenium remains an area that requires further investigation. Researchers have predominantly focused on the reduction of selenium to less toxic or harmless SeNPs and methylated selenium, but not all bacteria can reduce toxic oxyanions, and the resulting selenium species may not be methylated [98]. Moreover, there is currently limited information on the mechanisms of selenium resistance in bacteria, such as efflux and sorption of selenium oxyanions [98].

Interestingly, when use at the nanoscale, SeNPs have been shown to inhibit the dissemination of environmental antibiotic resistance genes, providing effective antibacterial properties without complicating the scale-up harvesting process [99]. As research into selenium’s antimicrobial potential continues, it is crucial to expand our understanding of microbial resistance mechanisms to ensure the effective and sustainable use of selenium-based treatments.

6.2 Variability in selenium availability in different population

Variability in selenium intake across the globe is influenced by several factors, including selenium concentration in soil, as well as factors affecting its availability in the food chain, such as the type of selenium, soil pH, organic matter content, and the presence of ions [100]. Most of Europe has lower selenium content in the soil compared to the United States, with Eastern Europe having a lower selenium intake than Western Europe. It is estimated that 15% of the global population experiences selenium deficiency, and selenium intake varies significantly between countries. Dietary selenium intake is approximately 40 μg per day in Europe, while in the USA, daily selenium intake ranges from 93 μg/day in women to 134 μg/day in men [101, 102].

Considering gender differences, the recommended daily selenium allowance in the United Kingdom is 75 μg/day for men and 60 μg/day for women [103]. This variability in selenium intake across different regions can lead to deficiency-related diseases in areas where intake is insufficient. Consequently, populations in these areas become more vulnerable to infectious disease due to the inadequate selenium consumption.

7. Conclusions

Selenium has been demonstrated to possess antimicrobial properties against various public health pathogens. In addition, its potential to modulate immune responses, generate ROS, and disrupt microbial processes highlights its importance in the fight against infectious diseases. Despite these promising findings, challenges remain, such as bioavailability, toxicity, and development of microbial resistance. Overcoming these obstacles necessitates further research, collaboration, and well-designed clinical trials. As we deepen our understanding and develop innovative solutions, selenium may emerge as a vital addition to our arsenal of antimicrobial agents, playing a crucial role in safeguarding public health, especially in light of rising antimicrobial resistance.