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REVIEW ARTICLE
Year : 2021  |  Volume : 14  |  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 Submission08-May-2020
Date of Decision17-Jul-2020
Date of Acceptance07-Aug-2020
Date of Web Publication22-Jan-2021

Correspondence Address:
Joyeta Ghosh
Department of Dietetics and Nutrition, NSHM Knowledge Campus, MAKAUT, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_236_20

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  Abstract 


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

How to cite this URL:
Ghosh J. Potential role of Vitamin D as an antiviral agent. Med J DY Patil Vidyapeeth [serial online] 2021 [cited 2021 Feb 28];14:3-12. Available from: https://www.mjdrdypv.org/text.asp?2021/14/1/3/307667




  Introduction Top


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.[1] 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).[2] 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.[1] 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.[3]

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.”[4] Consequently, Vitamin D acts as the key holder in terms of modulating systemic inflammation, oxidative stress, and mitochondrial respiratory functions.[5] 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.[6]

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.[7] 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.”[8] Vitamin D is regulating >200 genes, including genes associated with cell proliferation, differentiation, and apoptosis.[9] 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.[9] Therefore, Vitamin D emerges to be an important immunomodulator, playing a crucial role in regulating chemokine production and inflammation,[10],[11],[12] most efficient function of Vitamin D as an antiviral agent. Almost every single cell of human subject has the expression of Vitamin D receptor.[13] Both mononuclear cell lines and polynuclear cell lines have Vitamin D-mediated immunomodulatory activity through proper VDR expression.[14] The active form of Vitamin D lean to benify the mononuclear phenotype, through increasing VDR expression on monocytes and macrophages.[13],[15] 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).[16] This situation also helps to prevent excessive expression of inflammatory cytokines. In the case of neutrophils, Vitamin D also facilitates motility and phagocytic function.[17] 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.[18] Studies on mice also demonstrate that blocking TLR9 might be useful in treating human sepsis.[19] Aside from this, Vitamin D has a significant effect on T-cell activation and functionality of the antigen-presenting cells, chiefly on dendritic cells.[20] 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).[21]

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.[22],[23],[24] RSV is also responsible for causing asthma exacerbations in adults, especially in the elderly.[25] Whereas the rhinoviruses (RVs) are the persistent origin of common cold and asthma.[26] Vitamin D deficiency is significantly associated with acute asthma in children and adolescents.[27],[28] Deficiency or insufficiency of Vitamin D is also common in adult asthma patients and most pronounced in patients with severe or uncontrolled asthma.[29] 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.[30],[31],[32],[33],[34]

Worldwide, Vitamin D deficiency is becoming a public health concern and its deficiency is associated with several adverse health outcomes.[35] 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.[36] 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.[37] 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 Top


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 Top


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.[38],[39] Most of the cells have inbuilt VDR expressions and initiate production of AMPs after receiving stimulation from 25(OH) D.[40],[41] Epidemiological studies in the USA reveals that there is a positive relationship between serum Vitamin D level and cathelicidin levels among acute septicemia patients.[18],[42]

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.[38] Reports exhibit that cathelicidin is one of the potent antiviral agents against RSVs such as influenza and RSV.[43],[44],[45] 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.[46],[47],[48],[49]

Cathelicidin's expression can be downregulated while serum 25(OH)D level is below 20 ng/ml,[18] and it is associated with higher susceptibility to nosocomial infections such as pneumonia, sepsis, and central line infection.[21] 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.[42] In addition, AMPs play an important role in wound healing and clearance of bacteria and viruses at barrier sites.[50]


  Antiviral Efficacy against Different Viruses Top


One of the most common reasons for hospitalization among the elderly and children is acute lower respiratory infection.[51] Vitamin D has a protective role in influenza.[15],[32] Other viral infections where Vitamin D has a protective role include acquired immunodeficiency syndrome (AIDS) in human immunodeficiency viruses (HIV),[52] Asian flu,[53] hepatitis,[54] 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.[55] 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.[56] Again, the peak solstices after winter,[57] and thus it has more clinical extremity with lower UVB exposure.[17] Research has also proved that low Vitamin D levels may reduce AMP synthesis, which then is less likely to impede the influenza virus,[16],[58] having relative risk of influenza of 0.36 for those consuming 1200 IU/day compared with those having 200 IU/day.[32] 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).[31]

Seasonal disparity in Vitamin D production among children might explain the seasonality of respiratory infection among them.[59] 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.[60] In India, under-5 children predisposes subclinical Vitamin D deficiency, which is one significant marker for severe acute lower respiratory tract infection.[61] 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.[62],[63] 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.[64] 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.[65] 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.[60] A similar seasonal pattern is also seen among other RSVs, such as RSV and para influenza 1 and 2 viruses,[66] even though the occurrence of RSV infection is mostly related with the presence of humidity and temperature, compared to the percentage of UBV exposure.[67] Without jeopardizing viral clearance, Vitamin D seems to reduce the inflammatory response to infections due to RSV.[68] Thus, the immunomodulatory functions of Vitamin D play a crucial role in terms of acute lower respiratory tract disease severity,[51] give protection against asthma. Another randomized controlled trial shows similar protective role of Vitamin D against asthma.[32] Children who are suffering from asthma, also having low serum 25(OH)D level, cognate with high use of corticosteroids.[69] 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.[70]

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.[71] Thus it helps in proper monitoring on passage of substances across the tissue barrier.[72] Therefore, “VDR deletion leads to destruction of tight and adherence junction in lungs.”[73] Downregulation of VDR mRNA expression in bronchial epithelial cell is caused by RV and RSVs.[57] In addition, they limit the functional activity of calcitriol (active form of Vitamin D) by reducing the VDR numbers.[57] 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.[57] 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.[57]

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).[39] 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.[74] The influenza viruses (like rhino viruses) remains active against various AMPs as it lacks one lipoprotein envelop, essential for proper antimicrobial activity of AMPs.[75] 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.[76]

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.[77] Consequently, the VDR gene polymorphism plays a crucial role in the susceptibility of HIV infection, CD4 count, immunological hyperactivity, and severity of disease progression.[52],[78] 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.[79],[80] 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.[81] 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.[77] Regarding the treatment perspectives, both nonnucleoside reverse transcriptase inhibitor and protease inhibitor cause hyperthyroidism, closely linked with Vitamin D deficiency status.[82] After the beginning of highly active antiretroviral therapy, the serum Vitamin D level has no effect on CD4 cell recovery.[77]

The Vitamin D replete state remains beneficial during the occurrence of hepatitis.[36] VDR polymorphism is common in case of chronic hepatitis B development, highly associated with higher viral load, disease severity, and progression.[83] Considering positive response in hepatitis B or dengue viruses, the t allele (dimorphism at position 352) is related with increased Th1 cellular immunity.[84],[85] 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.[86] 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.[87] 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.[88],[89] 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.[90] If CCR5 production is less, then, there is an increased vulnerability to HCV infection,[91] standing up for potential deleterious action in Vitamin D deficiency, favoring host infection through the aforementioned Th2 influence on CCR5.[92]

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].[93] A recent review regarding the role of Vitamin D has grouped those mechanisms into three categories: physical barrier, cellular natural immunity, and adaptive immunity.[94] 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.[95] Metabolites of 1,25-dihydroxyvitamin D have been reported to restore surfactant synthesis in alveolar Type-II cells.[94],[96] In addition, COVID-19 patients have a strong upregulation of cytokine and IFN production-induced pneumonia, with an associated cytokine storm syndrome.[97] Administration of Vitamin D reduces the expression of pro-inflammatory cytokines and upregulates the expression of anti-inflammatory cytokines by macrophages.[93],[98] Vitamin D is a potent modulator of adaptive immunity;[94],[99] 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.[100] 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.[101] In addition, 1,25(OH) 2D3 promotes induction of the T regulatory cells, thereby inhibiting inflammatory processes.[102]
Figure 1: Possible protective mechanisms of Vitamin D against COVID-19 infection

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  Vitamin D Dosage for Prevention/Treatment Top


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.[31],[32],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109] On the basis of observational studies, the indicated protective concentration should be of at least 40–50 ng/mL (100–125 nmol/L).[108],[109] 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.[93] 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;[110] 600 IU/day (15 μg/day) for the USA;[111] and 800 IU/day (20 μg/day for >70 years) for Europe.[112] 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)[110] recommendations for Vitamin D and the US Institute of Medicine (IOM) recommendations for Vitamin D,[112] 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[113] 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.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115] 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.[114],[115] 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.[114],[115] 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.[114],[115] 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.[114] 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.[114],[115]


  Conclusion Top


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,[106] 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.

Acknowledgment

The author acknowledges Dr. Subhasis Maity, Director, NSHM Knowledge Campus, Kolkata Group of Institutions, for the facilities provided.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014;21:319-29.  Back to cited text no. 1
    
2.
Sugimoto H, Shiro Y. Diversity and substrate specificity in the structures of steroidogenic cytochrome P450 enzymes. Biol Pharm Bull 2012;35:818-23.  Back to cited text no. 2
    
3.
Holick MF, Chen TC. Vitamin D deficiency: A worldwide problem with health consequences. Am J Clin Nutr 2008;87:1080S-6S.  Back to cited text no. 3
    
4.
Santos GC, Zeidler JD, Pérez-Valencia JA, Sant'Anna-Silva AC, Da Poian AT, El-Bacha T, et al. Metabolomic analysis reveals Vitamin D-induced decrease in polyol pathway and subtle modulation of glycolysis in HEK293T cells. Sci Rep 2017;7:9510.  Back to cited text no. 4
    
5.
Wimalawansa S. Vitamin D deficiency: Effects on oxidative stress, epigenetics, gene regulation, and aging. Biology 2019;8:30.  Back to cited text no. 5
    
6.
Ricca C, Aillon A, Bergandi L, Alotto D, Castagnoli C, Silvagno F. Vitamin D Receptor is necessary for mitochondrial function and cell health. Int J Mol Sci 2018;19:1672.  Back to cited text no. 6
    
7.
Selvaraj P, Afsal K, Harishankar M. Vitamin D and macrophage functions in tuberculosis. Macrophage 2015;2:e756.  Back to cited text no. 7
    
8.
Sertznig P, Dunlop T, Seifert M, Tilgen W, Reichrath J. Cross-talk between vitamin D receptor (VDR)- and peroxisome proliferator-activated receptor (PPAR)-signaling in melanoma cells. Anticancer Res 2009;29:3647-58.  Back to cited text no. 8
    
9.
Hughes DA, Norton R. Vitamin D and respiratory health. Clin Exp Immunol 2009;158:20-5.  Back to cited text no. 9
    
10.
Fukuoka M, Ogino Y, Sato H, Ohta T, Komoriya K, Nishioka K, et al. RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol). Br J Dermatol 1998;138:63-70.  Back to cited text no. 10
    
11.
Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: Modulation of innate and autoimmunity. J Mol Med (Berl) 2010;88:441-50.  Back to cited text no. 11
    
12.
Toubi E, Shoenfeld Y. The role of vitamin D in regulating immune responses. Isr Med Assoc J 2010;12:174-5.  Back to cited text no. 12
    
13.
Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D (3) receptor in the immune system. Arch Biochem Biophys 2000;374:334-8.  Back to cited text no. 13
    
14.
Eleftheriadis T, Antoniadi G, Liakopoulos V, Galaktidou G. The effect of paricalcitol on osteoprotegerin production by human peripheral blood mononuclear cells. J Rheumatol 2009;36:856-7.  Back to cited text no. 14
    
15.
Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998;66:5314-21.  Back to cited text no. 15
    
16.
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and Vitamin D. Epidemiol Infect 2006;134:1129-40.  Back to cited text no. 16
    
17.
Lorente F, Fontan G, Jara P, Casas C, Garcia-Rodriguez MC, Ojeda JA. Defective neutrophil motility in hypovitaminosis D rickets. Acta Paediatr Scand 1976;65:695-9.  Back to cited text no. 17
    
18.
Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Alterations in Vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med 2009;7:28.  Back to cited text no. 18
    
19.
Plitas G, Burt BM, Nguyen HM, Bamboat ZM, DeMatteo RP. Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis. J Exp Med 2008;205:1277-83.  Back to cited text no. 19
    
20.
Canning MO, Grotenhuis K, de Wit H, Ruwhof C, Drexhage HA. 1-alpha, 25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol 2001;145:351-7.  Back to cited text no. 20
    
21.
Bikle DD. Vitamin D and the immune system: Role in protection against bacterial infection. Curr Opin Nephrol Hypertens 2008;17:348-52.  Back to cited text no. 21
    
22.
Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749-59.  Back to cited text no. 22
    
23.
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360:588-98.  Back to cited text no. 23
    
24.
DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, et al. Viral load drives disease in humans experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med 2010;182:1305-14.  Back to cited text no. 24
    
25.
Westerly BD, Peebles RS Jr. Respiratory syncytial virus infections in the adult asthmatic mechanisms of host susceptibility and viral subversion. Immunol Allergy Clin N Am 2010;30:523-39.  Back to cited text no. 25
    
26.
Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ 1995;310:1225-9.  Back to cited text no. 26
    
27.
Brehm JM, Schuemann B, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS, et al. Childhood asthma management program research, G, Serum Vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol 2010;126:52-8.e55.  Back to cited text no. 27
    
28.
Gupta A, Sjoukes A, Richards D, Banya W, Hawrylowicz C, Bush A, et al. Relationship between serum Vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med 2011;184:1342-9.  Back to cited text no. 28
    
29.
Korn S, Hübner M, Jung M, Blettner M, Buhl R. Severe and uncontrolled adult asthma is associated with Vitamin D insufficiency and deficiency. Respir Res 2013;14:25.  Back to cited text no. 29
    
30.
Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the third national Health and nutrition examination survey. Arch Int Med 2009;169:384-90.  Back to cited text no. 30
    
31.
Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One 2010;5:e11088.  Back to cited text no. 31
    
32.
Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of Vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010;91:1255-60.  Back to cited text no. 32
    
33.
Camargo CA Jr., Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, et al. Randomized trial of Vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics 2012;130:e561-7.  Back to cited text no. 33
    
34.
Goodall EC, Granados AC, Luinstra K, Pullenayegum E, Coleman BL, Loeb M, et al. Vitamin D3 and gargling for the prevention of upper respiratory tract infections: A randomized controlled trial. BMC Infect Dis 2014;14:273.  Back to cited text no. 34
    
35.
Holick MF. Vitamin D: Evolutionary, physiological and health perspectives. Curr Drug Targets 2011;12:4-18.  Back to cited text no. 35
    
36.
Dixit A, Kumar N, Kumar S, Trigun V. Antimicrobial resistance: Progress in the decade since emergence of New Delhi metallo-β-lactamase in India. Indian J Community Med 2019;44:4-8.  Back to cited text no. 36
[PUBMED]  [Full text]  
37.
Dima A. Youssef, antimicrobial implications of Vitamin D dermato-endocrinology October/November/December 2011. Landes Biosci 2011;3:220-9.  Back to cited text no. 37
    
38.
Bartley J. Vitamin D: Emerging roles in infection and immunity. Expert Rev Anti Infect Ther 2010;8:1359-69.  Back to cited text no. 38
    
39.
Ginde AA, Mansbach JM, Camargo CA Jr., Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 2009;169:384-90.  Back to cited text no. 39
    
40.
Schwalfenberg GK. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 2011;55:96-108.  Back to cited text no. 40
    
41.
Alitalo A. Human anti-infectious defence may be enhanced by Vitamin D. Duodecim 2010;126:1127-34.  Back to cited text no. 41
    
42.
Routsias JG, Karagounis P, Parvulesku G, Legakis NJ, Tsakris A. In vitro bactericidal activity of human beta-defensin 2 against nosocomial strains. Peptides 2010;31:1654-60.  Back to cited text no. 42
    
43.
Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol 2013;94:40-9.  Back to cited text no. 43
    
44.
Currie SM, Findlay EG, McHugh BJ, Mackellar A, Man T, Macmillan D, et al. The human cathelicidin LL-37 has antiviral activity against respiratory syncytial virus. PLoS One 2013;8:e73659.  Back to cited text no. 44
    
45.
Barlow PG, Findlay EG, Currie SM, Davidson DJ. Antiviral potential of cathelicidins. Future Microbiol 2014;9:55-73.  Back to cited text no. 45
    
46.
Lai Y, Adhikarakunnathu S, Bhardwaj K, Ranjith-Kumar CT, Wen Y, Jordan JL, et al. LL37 and cationic peptides enhance TLR3 signaling by viral double-stranded RNAs. PLoS One 2011;6:e26632.  Back to cited text no. 46
    
47.
Singh D, Qi R, Jordan JL, San Mateo L, Kao CC. The human antimicrobial peptide LL-37, but not the mouse ortholog, mCRAMP, can stimulate signaling by poly(I:C) through a FPRL1 dependent pathway. J Biol Chem 2013;288:8258-68.  Back to cited text no. 47
    
48.
Takiguchi T, Morizane S, Yamamoto T, Kajita A, Ikeda K, Iwatsuki K. Cathelicidin antimicrobial peptide LL-37 augments interferon-beta expression and antiviral activity induced by double-stranded RNA in keratinocytes. Br J Dermatol 2014;171:492-8.  Back to cited text no. 48
    
49.
Hewson CA, Jardine A, Edwards MR, Laza-Stanca V, Johnston SL. Tolllike receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol 2005;79:12273-9.  Back to cited text no. 49
    
50.
White JH. Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: Past, present and future. J Steroid Biochem Mol Biol 2010;121:234-8.  Back to cited text no. 50
    
51.
McNally JD, Leis K, Matheson LA, Karuananyake C, Sankaran K, Rosenberg AM. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol 2009;44:981-8.  Back to cited text no. 51
    
52.
de la Torre MS, Torres C, Nieto G, Vergara S, Carrero AJ, Macías J, et al. Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 2008;197:405-10.  Back to cited text no. 52
    
53.
Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011;54:887-93.  Back to cited text no. 53
    
54.
Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 2005;6:135.  Back to cited text no. 54
    
55.
Young GA Jr., Underdahl NR, Carpenter LE. Vitamin D intake and susceptibility of mice to experimental swine influenza virus infection. Proc Soc Exp Biol Med 1949;72:695-7.  Back to cited text no. 55
    
56.
Grant WB, Garland CF. The role of vitamin D3 in preventing infections. Age Ageing 2008;37:121-2.  Back to cited text no. 56
    
57.
Hope-Simpson RE. The role of season in the epidemiology of influenza. J Hyg(Lond) 1981;86:35-47.  Back to cited text no. 57
    
58.
Telcian AG, Zdrenghea MT, Edwards MR, Laza-Stanca V, Mallia P, Johnston SL, et al. Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro. Antiviral Res 2017;137:93-101.  Back to cited text no. 58
    
59.
Grant WB. Variations in Vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii. Pediatr Infect Dis J 2008;27:853.  Back to cited text no. 59
    
60.
Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and Vitamin D in reducing case fatality rates from the 1918–1919 influenza pandemic in the United States. Dermatoendocrinol 2009;1:215-9.  Back to cited text no. 60
    
61.
Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical Vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr 2004;58:563-7.  Back to cited text no. 61
    
62.
Linday LA, Shindledecker RD, Tapia-Mendoza J, Dolitsky JN. Effect of daily cod liver oil and a multivitamin-mineral supplement with selenium on upper respiratory tract pediatric visits by young, inner-city, Latino children: Randomized pediatric sites. Ann Otol Rhinol Laryngol 2004;113:891-901.  Back to cited text no. 62
    
63.
Bahr GM, Eales LJ, Nye KE, Majeed HA, Yousof AM, Behbehani K, et al. An association between Gc (Vitamin D-binding protein) alleles and susceptibility to rheumatic fever. Immunology 1989;67:126-8.  Back to cited text no. 63
    
64.
Yamamoto N, Urade M. Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the hemagglutinin of influenza virus. Microbes Infect 2005;7:674-81.  Back to cited text no. 64
    
65.
Edlich RF, Mason SS, Dahlstrom JJ, Swainston E, Long WB 3rd, Gubler K. Pandemic preparedness for swine flu influenza in the United States. J Environ Pathol Toxicol Oncol 2009;28:261-4.  Back to cited text no. 65
    
66.
Fry AM, Curns AT, Harbour K, Hutwagner L, Holman RC, Anderson LJ. Seasonal trends of human parainfluenza viral infections: United States, 1990-2004. Clin Infect Dis 2006;43:1016-22.  Back to cited text no. 66
    
67.
Yusuf S, Piedimonte G, Auais A, Demmler G, Krishnan S, Van Caeseele P, et al. The relationship of meteorological conditions to the epidemic activity of respiratory syncytial virus. Epidemiol Infect 2007;135:1077-90.  Back to cited text no. 67
    
68.
Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol 2010;184:965-74.  Back to cited text no. 68
    
69.
Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum Vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol 2010;125:995-1000.  Back to cited text no. 69
    
70.
Linday LA, Shindledecker RD, Dolitsky JN, Chen TC, Holick MF. Plasma 25-hydroxyvitamin D levels in young children undergoing placement of tympanostomy tubes. Ann Otol Rhinol Laryngol 2008;117:740-4.  Back to cited text no. 70
    
71.
Martin TA, Das T, Mansel RE, Jiang WG. Enhanced tight junction function in human breast cancer cells by antioxidant, selenium and polyunsaturated lipid. J Cellular Biochem 2007;101:155-66.  Back to cited text no. 71
    
72.
Zhang YG, Wu S, Sun J. Vitamin D, Vitamin D Receptor, and Tissue Barriers. Tissue Barriers 2013;1:e23118.  Back to cited text no. 72
    
73.
Chen H, Lu R, Zhang YG, Sun J. Vitamin D receptor deletion leads to the destruction of tight and adherens junctions in lungs. Tissue Barriers 2018;6:1-3.  Back to cited text no. 73
    
74.
Avenell A, Cook JA, Maclennan GS, Macpherson GC. Vitamin D supplementation to prevent infections: A sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing 2007;36:574-7.  Back to cited text no. 74
    
75.
Zhang G, Ross CR, Blecha F. Porcine antimicrobial peptides: New prospects for ancient molecules of host defense. Vet Res 2000;31:277-96.  Back to cited text no. 75
    
76.
Yenamandra SP, Hellman U, Kempkes B, Darekar SD, Petermann S, Sculley T, et al. Epstein-Barr virus encoded EBNA-3 binds to Vitamin D receptor and blocks activation of its target genes. Cell Mol Life Sci 2010;67:4249-56.  Back to cited text no. 76
    
77.
Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173:2909-12.  Back to cited text no. 77
    
78.
Van Den Bout-Van Den Beukel CJ, Fievez L, Michels M, Sweep FC, Hermus AR, Bosch ME, et al. Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: Effects of antiretroviral therapy. AIDS Res Hum Retroviruses 2008;24:1375-82.  Back to cited text no. 78
    
79.
Nieto G, Barber Y, Rubio MC, Rubio M, Fibla J. Association between AIDS disease progression rates and the Fok-I polymorphism of the VDR gene in a cohort of HIV-1 seropositive patients. J Steroid Biochem Mol Biol 2004;89-90:199-207.  Back to cited text no. 79
    
80.
Barber Y, Rubio C, Fernández E, Rubio M, Fibla J. Host genetic background at CCR5 chemokine receptor and Vitamin D receptor loci and human immunodeficiency virus (HIV) type 1 disease progression among HIV-seropositive injection drug users. J Infect Dis 2001;184:1279-88.  Back to cited text no. 80
    
81.
Nevado J, Tenbaum SP, Castillo AI, Sánchez-Pacheco A, Aranda A. Activation of the human immunodeficiency virus type I long terminal repeat by 1 alpha, 25-dihydroxyvitamin D3. J Mol Endocrinol 2007;38:587-601.  Back to cited text no. 81
    
82.
Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 1996;2:1240-3.  Back to cited text no. 82
    
83.
Saito M, Eiraku N, Usuku K, Nobuhara Y, Matsumoto W, Kodama D, et al. ApaI polymorphism of Vitamin D receptor gene is associated with susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis in HTLV-1 infected individuals. J Neurol Sci 2005;232:29-35.  Back to cited text no. 83
    
84.
Li JH, Chen DM, Li Z, Liu Y, Gao JR, Zeng XJ, et al. Study on association between Vitamin D receptor gene polymorphisms and the outcomes of HBV infection. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006;23:402-5.  Back to cited text no. 84
    
85.
Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the Vitamin D receptor gene. J Infect Dis 1999;179:721-4.  Back to cited text no. 85
    
86.
Loke H, Bethell D, Phuong CX, Day N, White N, Farrar J, et al. Susceptibility to dengue hemorrhagic fever in Vietnam: Evidence of an association with variation in the Vitamin D receptor and Fc gamma receptor IIa genes. Am J Trop Med Hyg 2002;67:102-6.  Back to cited text no. 86
    
87.
Yano M, Ikeda M, Abe K, Dansako H, Ohkoshi S, Aoyagi Y, et al. Comprehensive analysis of the effects of ordinary nutrients on hepatitis C virus RNA replication in cell culture. Antimicrob Agents Chemother 2007;51:2016-27.  Back to cited text no. 87
    
88.
Petta S, Cammà C, Scazzone C, Tripodo C, Di Marco V, Bono A, et al. Low Vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 2010;51:1158-67.  Back to cited text no. 88
    
89.
Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl Int 2011;24:43-50.  Back to cited text no. 89
    
90.
Ho AS, Cheng CC, Lee SC, Liu ML, Lee JY, Wang WM, et al. Novel biomarkers predict liver fibrosis in hepatitis C patients: Alpha 2 macroglobulin, Vitamin D binding protein and apolipoprotein AI. J Biomed Sci 2010;17:58.  Back to cited text no. 90
    
91.
Falleti E, Bitetto D, Fabris C, Cussigh A, Fontanini E, Fornasiere E, et al. Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis. World J Gastroenterol 2010;16:3016-24.  Back to cited text no. 91
    
92.
Coenen M, Nattermann J. The role of CCR5 in HCV infection. Eur J Med Res 2010;15:97-101.  Back to cited text no. 92
    
93.
William BG, Henry L, Sharon LM, Carole AB, Christine BF, Jennifer LA, et al. Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020;12:988.  Back to cited text no. 93
    
94.
Rondanelli M, Miccono A, Lamburghini S, Avanzato I, Riva A, Allegrini P, et al. Self-care for common colds: The pivotal role of Vitamin D, Vitamin C, Zinc, and echinacea in three main immune interactive clusters (Physical Barriers, Innate and Adaptive Immunity) involved during an episode of common colds-practical advice on dosages and on the time to take these nutrients/botanicals in order to prevent or treat common colds. Evid Based Complement Alternat Med 2018;2018:5813095.  Back to cited text no. 94
    
95.
Bombardini T, Picano E. Angiotensin converting enzyme 2 as the molecular bridge between epidemiologic and clinical features of COVID-19. Can J Cardiol 2020;6:784.e1-784.e2  Back to cited text no. 95
    
96.
Rehan VK, Torday JS, Peleg S, Gennaro L, Vouros P, Padbury J, et al. 1Alpha, 25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha, 25-dihydroxy Vitamin D3: Production and biological activity studies in pulmonary alveolar type II cells. Mol Genet Metab 2002;76:46-56.  Back to cited text no. 96
    
97.
Susanna F, Jenny AH, Christian MH. COVID-19: Immunology and treatment options. Clin Immunol 2020;215:108448.  Back to cited text no. 97
    
98.
Gombart AF, Pierre A, Maggini S. A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients 2020;12:236.  Back to cited text no. 98
    
99.
Lelli D, Pérez Bazan LM, Calle Egusquiza A, Onder G, Morandi A, Ortolani E, et al. 25(OH) vitamin D and functional outcomes in older adults admitted to rehabilitation units: The safari study. Osteoporos Int 2019;30:887-95.  Back to cited text no. 99
    
100.
Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency among US adults: Prevalence, predictors and clinical implications. Br J Nutr 2018;119:928-36.  Back to cited text no. 100
    
101.
Deplanque X, Wullens A, Norberciak L. Prevalence and risk factors of Vitamin D deficiency in healthy adults aged 18-65 years in northern France. Rev Med Interne 2017;38:368-73.  Back to cited text no. 101
    
102.
Jolliffe DA, James WY, Hooper RL, Barnes NC, Greiller CL, Islam K, et al. Prevalence, determinants and clinical correlates of Vitamin D deficiency in patients with Chronic Obstructive Pulmonary Disease in London, UK. J Steroid Biochem Mol Biol 2018;175:138-45.  Back to cited text no. 102
    
103.
Hiemstra PS. The role of epithelial beta-defensins and cathelicidins in host defense of the lung. Exp Lung Res 2007;33:537-42.  Back to cited text no. 103
    
104.
Creery D, Weiss W, Graziani-Bowering G, Kumar R, Aziz Z, Angel JB, et al. Differential regulation of CXCR4 and CCR5 expression by interleukin (IL)-4 and IL-13 is associated with inhibition of chemotaxis and human immunodeficiency Virus (HIV) type 1 replication but not HIV entry into human monocytes. Viral Immunol 2006;19:409-23.  Back to cited text no. 104
    
105.
Rosenvinge MM, Gedela K, Copas AJ, Wilkinson A, Sheehy CA, Bano G, et al. Tenofovir-linked hyperparathyroidism is independently associated with the presence of Vitamin D deficiency. J Acquir Immune Defic Syndr 2010;54:496-9.  Back to cited text no. 105
    
106.
Palacios C, Gonzalez L. Is Vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol 2014;144:138-45.  Back to cited text no. 106
    
107.
Youssef DA, Ranasinghe T, Grant WB, Peiris AN. Vitamin D's potential to reduce the risk of hospital-acquired infections. Derm Endocrinol 2012;4:167-75.  Back to cited text no. 107
    
108.
Quraishi SA, Bittner EA, Blum L, Hutter MM, Camargo CA Jr. Association between preoperative 25-hydroxyvitamin D level and hospital-acquired infections following Roux-en-Y gastric bypass surgery. JAMA Surg 2014;149:112-8.  Back to cited text no. 108
    
109.
Laviano E, Sanchez Rubio M, Gonzalez-Nicolas MT, Palacian MP, Lopez J, Gilaberte Y, et al. Association between preoperative levels of 25-hydroxyvitamin D and hospital-acquired infections after hepatobiliary surgery: A prospective study in a third-level hospital. PLoS One 2020;15:e0230336.  Back to cited text no. 109
    
110.
Scientific Advisory Committee on Nutrition. Vitamin D and Health; 2016. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.Pdf. [Last accessed on 2020 Jun 15].  Back to cited text no. 110
    
111.
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC, USA: Institute of Medicine; 2011.  Back to cited text no. 111
    
112.
European Food Safety Agency. Dietary Reference Values for Vitamin D; 2016. Available from: http://www.efsa.europa.eu/en/efsajournal/pub/4547. [Last accessed on 2020 Jun 15].  Back to cited text no. 112
    
113.
Susan AL, Ann RW, Kevin DC, Judy LB, Joanne LF, Tash M, et al. Vitamin D and SARS-CoV-2 virus/COVID-19 disease. BMJ Nutr Prev Health 2020. [doi:10.1136/ bmjnph-2020-000089].  Back to cited text no. 113
    
114.
Laplana M, Royo JL, Fibla J. Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis. Gene 2018;678:384-94.  Back to cited text no. 114
    
115.
Makoui MH, Imani D, Motallebnezhad M, Azimi M, Razi B. Vitamin D receptor gene polymorphism and susceptibility to asthma Meta-analysis based on 17 case control studies. Ann Allergy Asthma Immunol 2020;124:57-69.  Back to cited text no. 115
    


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