|Year : 2021 | Volume
| Issue : 1 | Page : 3-12
Potential role of Vitamin D as an antiviral agent
Department of Dietetics and Nutrition, NSHM Knowledge Campus, Maulana Abul Kalam Azad University of Technology, West Bengal, India
|Date of Submission||08-May-2020|
|Date of Decision||17-Jul-2020|
|Date of Acceptance||07-Aug-2020|
|Date of Web Publication||22-Jan-2021|
Department of Dietetics and Nutrition, NSHM Knowledge Campus, MAKAUT, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Vitamin D has potential antimicrobial activity, the deficiency of which has deleterious effects on the general well-being and longevity, predisposing major public health problem worldwide. About 1 billion people have Vitamin D deficiency, which is prevalent among all ethnicities and age groups throughout the world. In addition, the incidence of antimicrobial resistance has emerged as a major threat to public health, and it is estimated to cause 10 million deaths annually by 2050 throughout the world. Vitamin D, as a mighty antimicrobial agent, may decrease the occurrence of infection through numerous pathways. Vitamin D strengthens innate immunity by modulating the production of various anti-microbial peptide (AMPs), cytokine, chemokines and interleukin responses. Vitamin D is responsible for the regulation of >200 genes, including cell proliferation, differentiation, and apoptotic genes. It acts as the key holder for modulating systemic inflammation, oxidative stress, and mitochondrial respiratory functions. Thus, a Vitamin D replete state appears to benefit most infections. As an antiviral agent, Vitamin D may constitute an inexpensive prophylactic option either by itself or as a synergistic agent during the treatment of different viral infections. The present review stipulates the importance of Vitamin D and its possible mechanisms against treating any kind of viruses. Relevant published articles were summarized by performing computerized literature searches (searches were made in PubMed/Medline, EMBASE, ScienceDirect, and Scirus) of different authentic databases using the following keywords: Vitamin D, VDR, infections, antimicrobial peptides, viruses, and COVID-19. The future for the sunshine vitamin as an antiviral agent looks brighter. More scientific proposition entailing in vitro, in vivo, or genomic studies are required to understand how important Vitamin D is against viral infections.
Keywords: Antimicrobial peptides, COVID-19, infections, viruses, Vitamin D, Vitamin D receptor
|How to cite this article:|
Ghosh J. Potential role of Vitamin D as an antiviral agent. Med J DY Patil Vidyapeeth 2021;14:3-12
| Introduction|| |
Vitamin D in a strict sense is not a vitamin, as it is synthesized by our body to meet its requirements during adequate exposure to sunlight. Previous research established that for the majority of the population, the principle source of Vitamin D is exposure of the skin to ultraviolet–B (UVB) radiation (290–315 nm). Vitamin D can be of two different forms: vitamin D3 or cholecalciferol (from sun exposure) and Vitamin D2 or ergocalciferol. The latter one is produced in various plant materials when they are exposed to UVB radiations. The 25(OH)D circulates in the blood bound to Vitamin D-binding protein and is an available indicator of Vitamin D status. For biological activation, the 25(OH)D is converted into 1,25-dihydroxyvitamin D (calcitriol) by the mitochondrial 1α-hydroxylase enzyme (CYP27B1). Primarily, the majority of the body's 1,25(OH) 2D3 is synthesized in renal tubules of the kidney, but numerous extrarenal sites in cells that express CYP27B1 are capable of synthesizing calcitriol as well.
Mitochondrion is one of the supreme parts of cellular functions. Vitamin D perceives a crucial role in regulating mitochondrial activity including the “redox homeostasis and protection against oxidative stress.” Consequently, Vitamin D acts as the key holder in terms of modulating systemic inflammation, oxidative stress, and mitochondrial respiratory functions. Other ways Vitamin D is responsible for protection against excessive cellular respiration, ROS production or cellular damage. Thus, the Vitamin D receptor (VDR) is an essential key to human health.
The past 100 years of research has shown one promising function of Vitamin D, which is modulating immune functions, mediated by monocytes, macrophages, dendritic cells, T cells, and B cells. In modern cell biology, Vitamin D in association with Vitamin A and oxidized lipids of omega-3 and 6 acts as an important signaling factor named as “superfamily of transacting transcriptional regulatory factors.” Vitamin D is regulating >200 genes, including genes associated with cell proliferation, differentiation, and apoptosis. It is observed that Vitamin D is active in a vast number of immune functions, related to cytokines, T cell, T helper cells, interleukin (IL)-1, -2, -4, -5, -10, -12, -17, interferon-β (IFN-β), CD14, etc. Therefore, Vitamin D emerges to be an important immunomodulator, playing a crucial role in regulating chemokine production and inflammation,,, most efficient function of Vitamin D as an antiviral agent. Almost every single cell of human subject has the expression of Vitamin D receptor. Both mononuclear cell lines and polynuclear cell lines have Vitamin D-mediated immunomodulatory activity through proper VDR expression. The active form of Vitamin D lean to benify the mononuclear phenotype, through increasing VDR expression on monocytes and macrophages., Accordingly, circulating Vitamin D levels possess direct impact on macrophages and escalate their “oxidative burst” potential (maturation and production of hydrogen peroxide, acid phosphatase, and cytokines). This situation also helps to prevent excessive expression of inflammatory cytokines. In the case of neutrophils, Vitamin D also facilitates motility and phagocytic function. Jeng et al. exhibit that Vitamin D may enhance the immune response by decreasing both local and systemic inflammatory responses and reduce the activation of toll-like receptor (TLR) among sepsis patients. Studies on mice also demonstrate that blocking TLR9 might be useful in treating human sepsis. Aside from this, Vitamin D has a significant effect on T-cell activation and functionality of the antigen-presenting cells, chiefly on dendritic cells. The cellular proliferation of T helper 1 (Th1) cell also inhibited by Vitamin 1,25-D3 (impairing production of IL-2, tumor necrosis factor-α and IFN).
The bronchial epithelial cells of respiratory system is the main seat of respiratory virus (RSV) infection. Studies show that RSV is the most common entity responsible for acute bronchiolitis in infants, and is also the principal reason of morbidity among children and elderly. These studies also suggest that the viral load is correlated with the severity of the diseases.,, RSV is also responsible for causing asthma exacerbations in adults, especially in the elderly. Whereas the rhinoviruses (RVs) are the persistent origin of common cold and asthma. Vitamin D deficiency is significantly associated with acute asthma in children and adolescents., Deficiency or insufficiency of Vitamin D is also common in adult asthma patients and most pronounced in patients with severe or uncontrolled asthma. The last 10 years of research work has already proved that Vitamin D deficiency is directly associated with increased rate of respiratory viral infections and also Vitamin D supplementation might decrease the occurrence of respiratory tract infections.,,,,
Worldwide, Vitamin D deficiency is becoming a public health concern and its deficiency is associated with several adverse health outcomes. In addition, the incidence of antimicrobial resistance has emerged as a major threat to public health, and it is estimated to cause 10 million deaths annually by 2050 throughout the world. As an antiviral agent, Vitamin D may constitute an inexpensive prophylactic option either by itself or as a synergistic agent during the treatment of different viral infections. The world is facing serious COVID-19 pandemic, and millions of people from all over the world are getting affected with high mortality rates. Every single country has an urge to find out an alternative treatment against these viruses. Such environment has provided a new opportunity to review the antiviral potential of this century-old remedy for the human immune system. The current review signifies the possible mechanisms of Vitamin D responsible for protection against viral invasion and replication inside the host cells. How this century-old nutrient is still efficient during treatment and recovery from viral infection is speculated here.
| Data Synthesis|| |
Relevant published articles were summarized by performing computerized literature searches (searches were made in Relevant published articles were summarized by performing computerized literature searches (searches were made in PubMed/Medline – www.ncbi.nim.nih.gov, EMBASE, ScienceDirect – www.sciencedirect.com, scholar.google.com, Scirus – www.scirus.com/srsapp)
of different authentic databases using the following keywords: Vitamin D, VDR, infections, antimicrobial peptides, viruses, and COVID-19. Potential studies with original or review data were selected and their important findings were incorporated into the following titled paragraphs.
| Antimicrobial Peptides and Vitamin D|| |
One of the major components of Vitamin D-mediated antimicrobial activity is through the production of peptides. Vitamin D plays a crucial role in the regulation of potent antimicrobial peptide (AMP) release (cathelicidin, β defensin 2) in natural killer cells, neutrophils, monocytes, and epithelial cell lining of the respiratory tract., Most of the cells have inbuilt VDR expressions and initiate production of AMPs after receiving stimulation from 25(OH) D., Epidemiological studies in the USA reveals that there is a positive relationship between serum Vitamin D level and cathelicidin levels among acute septicemia patients.,
One of the most potent AMPs is LL-37 or cathelicidin, which is lethal against a wide range of pathogens including different viruses as well. Reports exhibit that cathelicidin is one of the potent antiviral agents against RSVs such as influenza and RSV.,, In the field of virology, it has been observed that cathelicidin mostly escalates viral double-strand RNA TLR-3 signaling and extends IFN-β expression. It also enhances the RV-induced cytokine production in BEAS-2B cells (bronchoepithelial cells) via activating TLR3.,,,
Cathelicidin's expression can be downregulated while serum 25(OH)D level is below 20 ng/ml, and it is associated with higher susceptibility to nosocomial infections such as pneumonia, sepsis, and central line infection. Human beta-defensin-2 is another AMP, regulated by Vitamin D. Many projects (in vitro studies) are ongoing exploring its positive action against multidrug-resistant microbes. In addition, AMPs play an important role in wound healing and clearance of bacteria and viruses at barrier sites.
| Antiviral Efficacy against Different Viruses|| |
One of the most common reasons for hospitalization among the elderly and children is acute lower respiratory infection. Vitamin D has a protective role in influenza., Other viral infections where Vitamin D has a protective role include acquired immunodeficiency syndrome (AIDS) in human immunodeficiency viruses (HIV), Asian flu, hepatitis, and others.
As for evidence, back to the 1940s, there is one report which observed that experimental influenza viruses on mice has a significant association with poor Vitamin D diet. Research work from Western countries exhibits that most of the epidemic zones such as America and Europe reach their peak influenza outbreak during December through March, mostly when the UVB radiation exposure is less and human serum level of 25(OH)D is lowest in the population. Again, the peak solstices after winter, and thus it has more clinical extremity with lower UVB exposure. Research has also proved that low Vitamin D levels may reduce AMP synthesis, which then is less likely to impede the influenza virus,, having relative risk of influenza of 0.36 for those consuming 1200 IU/day compared with those having 200 IU/day. As seasonal variations play a crucial role in maintaining optimum Vitamin D level, another work demonstrated that during winter session, maintaining the Vitamin D serum concentration of about 38 ng/mL or above should remarkably decrease the occurrence of acute viral respiratory tract infections (including influenza).
Seasonal disparity in Vitamin D production among children might explain the seasonality of respiratory infection among them. Again, in the 1918–1919 influenza pandemic, the USA had inverse correlations between the case fatality rates and the average 25(OH)D status of the common people. In this study, the Vitamin D status was represented by solar UBV doses. In India, under-5 children predisposes subclinical Vitamin D deficiency, which is one significant marker for severe acute lower respiratory tract infection. Linday et al. provided an evidence-based report, which exhibits that after the administration of Vitamin D supplementation dose, there was a remarkable decrease in respiratory tract infection rate from autumn through spring., During initiation of cell activation procedure, the B cell membranes continuously express serum Vitamin D3 binding protein (Gc), the forerunner of primary macrophage-activating factor (MAF), which remains low in patients having influenza virus infection. As their serum consists of α-N-acetylgalactosaminidase (Nagalase), it deglycosylates Gc protein and thus prevents MAF activity, contributing for immunosuppression. Considering the outbreaks of H<Subscript>1</Subscript>N<Subscript>1</Subscript> influenza in 2009, Edlich et al. strongly recommended to test and treat Vitamin D deficiency among health-care workers and patients as a preventive measure. Pro-inflammatory cytokine production is also regulated by Vitamin D, thus playing a crucial role in recovery from cytokine storm in H<Subscript>1</Subscript>N<Subscript>1</Subscript> infection. A similar seasonal pattern is also seen among other RSVs, such as RSV and para influenza 1 and 2 viruses, even though the occurrence of RSV infection is mostly related with the presence of humidity and temperature, compared to the percentage of UBV exposure. Without jeopardizing viral clearance, Vitamin D seems to reduce the inflammatory response to infections due to RSV. Thus, the immunomodulatory functions of Vitamin D play a crucial role in terms of acute lower respiratory tract disease severity, give protection against asthma. Another randomized controlled trial shows similar protective role of Vitamin D against asthma. Children who are suffering from asthma, also having low serum 25(OH)D level, cognate with high use of corticosteroids. Another study report shows that while the target group is having 50% deficient and 31% insufficient serum 25(OH)D level, the chances of the deficient one getting recurrent otitis media are higher than that of the sufficient one.
For a healthy respiratory system, “tight cell junction” is crucial during infectious stage. Vitamin D is one of the most competent micronutrients that helps to maintain “tight cell junction” and strengthens the protective function of endothelial cells. Thus it helps in proper monitoring on passage of substances across the tissue barrier. Therefore, “VDR deletion leads to destruction of tight and adherence junction in lungs.” Downregulation of VDR mRNA expression in bronchial epithelial cell is caused by RV and RSVs. In addition, they limit the functional activity of calcitriol (active form of Vitamin D) by reducing the VDR numbers. Anyhow, if calcitriol is exogeneously added to the culture medium (epithelial cell line), it increases cathelicidin gene expression and other important intracellular components, critical in controlling viral replication, especially through upregulating the RV1B-induced ISGs. The important finding was that other than the downregulation of VDR expression, the RSV and RV are upregulated the 1α(OH)ase expression and lower the 24(OH)ase expression. Overall, these viruses try to inhibit the functionality of Vitamin D inside the epithelial cells, thereby creating a favorable environment for long survivability. The study proves that Vitamin D reduces replication of RVs inside the cells. Alternatively, it increases the cathelicidin expression more, which is one potent antirhinoviral activity. Rhinovirus-infected epithelial cells lower VDR levels, but exogenous Vitamin D supplementation has proven to significantly restore the antiviral defenses via cathelicidin and innate IFN pathways.
Epidemiological studies observe that individuals, who have serum 25(OH)D levels <10 ng/mL, have 55% more chances of having upper respiratory infections than individuals with sufficient one (>30 ng/mL). For elderly population, Vitamin D level should be at greater concentration and needs to be sufficient so that they can cope up with proper antiviral functions as these population always complain of poor immune responses. The influenza viruses (like rhino viruses) remains active against various AMPs as it lacks one lipoprotein envelop, essential for proper antimicrobial activity of AMPs. Epstein–Barr viruses alter the B lymphocytes cell into immortalized lymphoblasts. In this case, the VDR protein remains as the binding partner to Epstein–Barr virus nuclear antigen 3 (EBNA-3). The EBNA-3 acts as a modulator of cell transcription and viral genes. Along with that, it blocks the VDR-dependent gene activation and thereby protects the lymphoblast cell lines against Vitamin D3-mediated cell apoptosis.
Vitamin D plays a defensive role against HIV; either by promoting the release of antiviral elements such as β-defensin 2 and cathelicidin (directly effective) or indirectly through VDR activity. Consequently, the VDR gene polymorphism plays a crucial role in the susceptibility of HIV infection, CD4 count, immunological hyperactivity, and severity of disease progression., VDR gene polymorphism (VDR BsmI BB and FokI heterozygosities) is common in patients suffering from AIDS, strongly related with high amount of CD4 drop and rapid progression to AIDS., Anyway, in such conditions, the Vitamin D pathway can be intimated in advancing disease progress. Nevado et al. utilized U937 cells for a model of mononuclear cells (a target for HIV) and revealed that calcitriol and VDR have a crucial impact on transactivation of the prolonged repeat sequence of HIV type I, a pivotal element in viral replication. The chemokine receptor CCR5 plays a crucial role during the invading procedure of HIV into monocytes. Vitamin D plays a dual protective role against HIV; either it blocks the infectious pathway by promoting Th2 response or induces cytokine release (IL-13), thereby regulating the CCR5 expression. Other ways Vitamin D control the RANTES production (a natural ligand of CCR5 protect against viral entry). A study revealed that Vitamin D status is linked with the significance of highly active antiretroviral therapy. It has been observed that serum Vitamin D level had significantly reduced in white nonnucleoside reverse transcriptase inhibitor-treated individuals than in those treated with protease inhibitor. Regarding the treatment perspectives, both nonnucleoside reverse transcriptase inhibitor and protease inhibitor cause hyperthyroidism, closely linked with Vitamin D deficiency status. After the beginning of highly active antiretroviral therapy, the serum Vitamin D level has no effect on CD4 cell recovery.
The Vitamin D replete state remains beneficial during the occurrence of hepatitis. VDR polymorphism is common in case of chronic hepatitis B development, highly associated with higher viral load, disease severity, and progression. Considering positive response in hepatitis B or dengue viruses, the t allele (dimorphism at position 352) is related with increased Th1 cellular immunity., Some preliminary research has shown a positive effect of Vitamin D against hepatitis C virus infection (HCV). Patients having HCV reveal that Vitamin D2 (but not D3) hinders viral RNA replication, hypothetically by inducing oxidative burst, similar with cyclosporine activity. Risk factors such as severe fibrosis and low sustained viral response to IFN can be more fatal to chronic HCV patients (genotype I) having low serum Vitamin D level. Consequently, Vitamin D supplementation ameliorates the probability of attaining a sustained response after treatment with antiviral agent such as IFFN-α and ribavirin. Further, the most important biomarker of liver fibrosis is Vitamin D-binding protein, higher level of which indicates normal stage, mild fibrosis stage and the lower in the advanced stage. Thus, liver fibrosis can be detected by estimating Vitamin D-binding protein, without conducting biopsy., Thus, Vitamin D has a direct influence on liver cirrhosis and fibrosis as well. VDR genetic polymorphism has a significant impact on the occurrence of hepatocellular carcinoma, in patients having liver cirrhosis, which is more fatal in alcoholic patients. If CCR5 production is less, then, there is an increased vulnerability to HCV infection, standing up for potential deleterious action in Vitamin D deficiency, favoring host infection through the aforementioned Th2 influence on CCR5.
At present, the world is in the clutch of the COVID-19 pandemic. Public health measures that can decrease the risk of disease and fatality in addition to quarantines are desperately required. Many research reports are predicting the possible protective role of Vitamin D against COVID-19 [Figure 1]. A recent review regarding the role of Vitamin D has grouped those mechanisms into three categories: physical barrier, cellular natural immunity, and adaptive immunity. The primary target of coronaviruses are the Type-II pneumocytes and ACE2 (angiotensin-converting enzyme 2) receptors, which are highly expressed on these cells. Weakened function of Type-II pneumocytes decreases the surfactant level and extend surface tension in COVID-19. Metabolites of 1,25-dihydroxyvitamin D have been reported to restore surfactant synthesis in alveolar Type-II cells., In addition, COVID-19 patients have a strong upregulation of cytokine and IFN production-induced pneumonia, with an associated cytokine storm syndrome. Administration of Vitamin D reduces the expression of pro-inflammatory cytokines and upregulates the expression of anti-inflammatory cytokines by macrophages., Vitamin D is a potent modulator of adaptive immunity;, 1,25(OH) 2D3 conquers responses mediated by the T helper cell type 1 (Th1),T helper cell type 1 (Th1), subdues the production of inflammatory cytokines IL-2 and INF gamma. Furthermore, 1,25(OH) 2D3 aids cytokine production by the T helper type 2 (Th2) cells, which ultimately enhances the indirect suppression of Th1 cells by complementing this with actions mediated by a multitude of cell types. In addition, 1,25(OH) 2D3 promotes induction of the T regulatory cells, thereby inhibiting inflammatory processes.
|Figure 1: Possible protective mechanisms of Vitamin D against COVID-19 infection|
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| Vitamin D Dosage for Prevention/Treatment|| |
Reports suggest that the Vitamin D supplementation to raise serum 25(OH)D concentrations can help in decreasing the rate of many different infections, including viral one.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, On the basis of observational studies, the indicated protective concentration should be of at least 40–50 ng/mL (100–125 nmol/L)., All people in the hospital, including patients and staff, should take Vitamin D supplements to raise 25(OH)D concentrations as an important step in preventing infection and spread during the COVID-19 pandemic. Trials on that hypothesis would be worth conducting.
Most countries have existing health recommendations as to Vitamin D intakes, yet a significant proportion of populations are often deficient and/or insufficient. Supplementation with Vitamin D according to different government guidelines varies, for example, 400 IU/day (10 μg/day) for the UK; 600 IU/day (15 μg/day) for the USA; and 800 IU/day (20 μg/day for >70 years) for Europe. All of these recommendations were inveterate to ensure that 25(OH)D concentrations in the majority of the population should remain above 25 nmol/L (UK) in order to safeguard musculoskeletal health or above 30 nmol/L (USA) to minimize the risk of Vitamin D deficiency (the USA recommendation was also established to optimize musculoskeletal health in the population using a 25OHD concentration of 50 nmol/L). Supplementation with Vitamin D is especially important and crucial too during the times of self-isolation associated with limited sunlight exposure. This is in compliance with the UK Scientific Advisory Committee on Nutrition (SACN) recommendations for Vitamin D and the US Institute of Medicine (IOM) recommendations for Vitamin D, both of which were orthodox under the assumption of minimal exposure to sunlight. Consequently, re-emphasis of advice on safe sun exposure (below) and holding up the government advice on supplements especially when sunlight exposure is low would further improve the Vitamin D status. The UK SACN, US IOM, and EU European Food Safety Agency recommend that Vitamin D intake (total from both foods and dietary supplements) should be limited to 4000 IU/day (100 μg/day) for adults, and there is broad international consensus that people should avoid higher dose supplements that risk total intake from all sources exceeding this level as Vitamin D toxicity is another important health concern.
Vitamin D receptor Polymorphism
Vitamin D is crucial in regulating the immune response against viral infection.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, In this regard, Vitamin D deficiency may increase the vulnerability to enveloped virus infection such as HIV, hepatitis, dengue, and respiratory syncytial virus infection, among others., Vitamin D activity is conciliated by its receptor (VDR), which acts as a transcription factor modulating the expression of genes triggering the response against viruses., Till date, six major VDR polymorphisms (Cdx, A1012G, FokI, BsmI, ApaI, and TaqI) have been considered in the context of viral infection susceptibility. Reported studies show contentious results probably due to statistical lack of power and population genetic differences., Some research reports may have been underpowered to uncover small allelic effects, which is often quite common among complex traits such as those involving host–pathogen interactions. Furthermore, among markers analyzed, FokI polymorphism came out as consistently associated with susceptibility to infection to RSV. An usual trend is observed between the worldwide incidence of RSV infection and FokI allele frequency distribution that points toward FokI polymorphism as a candidate genetic factor contributing to worldwide regional differences on RSV incidence. There is no study yet conducted on COVID-19 virus. Several meta-analyses suggest that VDR gene polymorphism is associated with the risk of asthma/viral infections.,
| Conclusion|| |
The future for the sunshine vitamin as an antiviral agent looks brighter. More scientific proposition entailing in vitro, in vivo, or genomic studies are required to understand how important Vitamin D is against viral infections. Considering the situation that most people have insufficient levels of Vitamin D and that >1 billion people worldwide are having deficiency, properly designed supplementation studies on humans will be indicative for dictating gain from optimizing serum Vitamin D level on immune function. It will be very much engrossing to understand whether sufficient serum Vitamin D level will be beneficial in treating any kind of viral infection. Overall, Vitamin D may contribute as a cost-effective option from the treatment perspective, either as a sole agent or as an adjunct to the current antimicrobial agents.
The author acknowledges Dr. Subhasis Maity, Director, NSHM Knowledge Campus, Kolkata Group of Institutions, for the facilities provided.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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