Open access peer-reviewed chapter - ONLINE FIRST

Vitamin D Deficiency as a Risk Factor in Infectious Diseases Development

Written By

Larisa M. Marusca, Flavia A.E. Szekely, Delia I. Horhat and Florin G. Horhat

Submitted: 22 May 2023 Reviewed: 02 June 2023 Published: 11 June 2025

DOI: 10.5772/intechopen.112069

Vitamins and Human Health IntechOpen
Vitamins and Human Health Edited by Julia Fedotova

From the Edited Volume

Vitamins and Human Health [Working Title]

Associate Prof. Julia Fedotova

Chapter metrics overview

14 Chapter Downloads

View Full Metrics

Abstract

In the latest years, researchers demonstrated a two-way interaction between a balanced diet with sufficient essential micronutrients and the immune response. Unbalanced nutrition can cause a micronutrient deficiency, affecting the susceptibility and severity of infections. It is well known that micronutrients such as vitamins (A, C, D, E, B6, and B12), folic acid, iron, copper, zinc, and minerals play a vital role in the immune system, having a direct influence on antibody formation. From all the micronutrients analyzed, vitamin D has the most important influence on the immune system by regulating innate and adaptive immune responses in bacterial, viral, or fungal infections. All the studies published highlight a strong connection between vitamin D deficiency and the pathogenesis of several infectious diseases.

Keywords

  • vitamin deficiency
  • vitamin D
  • infectious diseases
  • bacterial infections

1. Introduction

The study of the main cause of rickets, a condition characterized by skeletal deformities and known as “the English disease,” brought to the discovery of vitamin D and the connection of its deficiency with the development of this condition [1, 2].

In recent years, a growing number of studies have been published highlighting the importance of a well-balanced diet for maintaining a healthy body due to the involvement of micronutrients such as vitamins and minerals in all the biochemical and immunological processes [3, 4, 5]. Of all these micronutrients, vitamin D plays a critical role and is an essential micronutrient for human health. Due to the high prevalence of vitamin D deficiency and the potential role of this deficiency in the etiopathogenesis of many diseases, a multitude of research studies have been conducted worldwide. All their results demonstrated and explained the role of this vitamin in different illnesses such as osteoporosis, autoimmune diseases, different cancers, cardiovascular pathologies, and infectious diseases [6, 7].

The SARS-COV-2 pandemic has been one of the most important worldwide challenges affecting everyday life. All the studies conducted since the begging of this pandemic showed that the complications of the lower respiratory tract had a higher prevalence for patients with vitamin D deficiency, a deficiency caused by food and changing habits during the pandemic. Also, some meta-analyses showed that vitamin D supplementation had a beneficial role by reducing severe complications and enhancing anti-inflammatory, antioxidant, and immunomodulatory responses in SARS-COV2 infections [8, 9].

Advertisement

2. Vitamin D metabolism

Vitamin D, a fat-soluble steroid hormone, is mainly responsible for controlling the absorption and homeostasis of calcium, magnesium, and phosphate. Also, it has an important role in regulating immune and inflammatory responses and maintaining human health [9]. Vitamin D exists in two forms: cholecalciferol (or vitamin D3), found in animal sources, and ergocalciferol (or vitamin D2), found in plant sources [2].

In humans, two sources of vitamin D production have been described. The first and main source also represents a unique property of this vitamin. The metabolic process of vitamin D starts in the skin from exposure to ultraviolet (UV) rays [6, 10, 11]. The second source of vitamin D is represented by a list of a few foods naturally enriched in vitamin D, but dermal synthesis remains the main source (90% of vitamin D replenishment) [2].

During exposure to UV irradiation (spectrum 280–320 UVB), 7-dehydrocholesterol (7-DHC) found in the skin is converted to pre-vitamin D3 (pre-D3), which isomerizes to vitamin D3 in a thermos-sensitive process. The rate of D3-formation depends on UVB intensity, which varies to season or latitude and level of skin pigmentation (UVB can be blocked by the quantity of melanin in the skin). Also, sunscreen and clothing can limit D3 production [2, 6].

Vitamin D3 synthesized in the skin is biologically inactive and needs further enzymatic conversion in order to activate. After binding to vitamin D binding protein (VDBP), D3 enters the lymphatic system and venous blood. Through the circulatory system, D3 undergoes in the liver 25-hydroxylation to 25-hydroxyvitamin D (25(OH)D), which represents the most important circulating form of vitamin D. Its plasma level is used as a biomarker for VB status. Further, a second hydroxylation of 25(OH)D turns into calcitriol (1,25(OH)2D—most active form) through 1-alpha-hydroxylation at the kidney level. Parathyroid hormone (PTH) plays an important role in regulating this process. Also, growth hormone or hypophosphatemia may be involved in this process. Enzyme 1-alpha-hydroxylase is primarily found in kidneys, but its presence has also been described in other places with the possible autocrine-paracrine role of 1,25(OH)2D such as alveolar macrophages, osteoblasts, lymph nodes, placenta, colon, or breasts [2, 12].

When it comes to dietary intake, VD is produced in much smaller proportions because few foods naturally contain forms of VD. D2 is produced from ergosterol found in plants and fungi (e.g., mushrooms) under UVB irradiation, while D3 is found in oily fish. Because of molecular structure differences between D3 and D2, D2 has a lower affinity to DBP with a faster clearance from the circulation and a limited conversion to 25 (OH)D [2, 11].

Advertisement

3. Vitamin D deficiency

Even though vitamin D positively impacts human health, deficiency of this vitamin is still common, according to epidemiological studies. It is estimated that almost 50% of the population across the world has vitamin D deficiency. Institute of Medicine (IOM) has recommended values of 25(OH)D between 21 and 29 ng/mL or less than 0.8 IU in order to define a VDD [6, 7, 10].

The most important VD source for children and adults is represented by exposure to natural sunlight. Studies have shown that sunscreen with an SPF of 30 can reduce by more than 95% the VD synthesis. Also, people with naturally dark skin tones require longer exposure than white people, and body mass index (BMI) is associated with a deficiency of VD. Low levels of VD determine abnormalities in calcium, phosphorus, and bone metabolism by decreasing the absorption of dietary calcium and phosphorus associated with increased PTH levels. These metabolic deficiencies increase osteoclastic activity, resulting in osteopenia and osteoporosis. In younger children, this process causes a little mineralization of their skeleton, resulting in a variety of skeletal deformities known as rickets. Also, the latest research has suggested a correlation of VD serum levels with the occurrence or aggravation of many pediatric diseases. Childhood autism, obesity, asthma, or rickets represent a part of pediatric diseases, which are associated with VD deficiency [1, 2].

There are some groups at risk of VD deficiency because of difficulty obtaining sufficient VD from natural food sources, and dietary supplements may be required to maintain a healthy VD status. Breastfed infants, older adults, people with limited sun exposure or with dark skin, people with fat malabsorption, obese people or those who have undergone gastric bypass surgery, patients with nephritic syndrome, with chronic granuloma-forming disorders, lymphomas, primary hyperparathyroidism, patients treated with a variety of medications including anticonvulsants, or for AIDS/HIV treatment, represent risk groups to develop VD deficiency [7, 11].

Some prevention and treatment strategies should be implemented. Serial monitoring of 25(OH)D and serum calcium levels should be recommended. Also, additional VD through supplementation is the best way to get additional VD. There are studies suggesting supplementation with about 800 IU/per day of VD may reduce hip and nonspinal fractures [6].

Advertisement

4. Vitamin D and the immune system

The immune system is formed of two distinct types of immunity: innate and adaptive. When it comes to the stimulation of innate immunity, it is the activation of toll-like receptors (TLRs) in macrophages, monocytes, polymorphonuclear cells (PMNs), and several epithelial cells. TLRs are a transmembrane pathogen-recognition receptor that interacts with specific membrane structures presented on the surface of infectious agents that trigger the innate immune response in the host. TLRs activation induces the production of antimicrobial peptides (cathelicidin and reactive oxygen species). When TLRs are stimulated by an infectious organism in macrophages, an increase of CYP27B1 and VDR expression occurs. If there is an adequate substrate (25OHD) for activated VDRs, it will determine a cathelicidin induction. Therefore, it can be assumed that adequate levels of VD promote an innate immune response [11].

T and B lymphocytes, cells specialized in antigen presentation, and dendritic cells (DC) are among the cells, which initiate an adaptive immune response. When it comes to this type of immune response, VD exerts, in general, an inhibitory action by decreasing the maturation of DC and decreasing their ability to present antigen and, therefore, to activate T cell lymphocytes. Also, it may suppress IL-12, IL-23, and IL-6 production necessary for T helper cell (Th) development and function by modulating their cytokine production. Also, there are in vitro studies demonstrating that 1,25(OH)2D promotes the differentiation of monocytes into macrophages in both human and mouse cells, suppresses the differentiation of monocytes into DC, and, by suppressing interleukin production, promotes the development of regulatory T-lymphocytes with suppressive activity [12, 13].

Other recent studies highlighted the importance of VD in enhancing pathogen elimination mechanisms by increasing the activity of macrophages and their monocyte precursors and by directly affecting the proliferation of B lymphocytes and the production of immunoglobulin [11, 13].

Understanding VD’s immune modulation mechanisms may explain its important role in infectious diseases. Many studies demonstrate the association of low levels of 25(OH)D in upper respiratory tract infections, tuberculosis, chronic obstructive pulmonary disease, cystic fibrosis, or human immunodeficiency virus. The effects of VD on the immune system suggest the importance of this vitamin in immune-mediated disorders in autoimmunity [11, 12, 13].

In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, epidemiologic studies revealed a lower prevalence of this disease in equatorial regions, which become higher with increasing latitude. Lack of sunshine in high-latitude regions and, therefore, low levels of cutaneous VD synthesis suggest a potential risk factor deficiency of VD. The same epidemiological studies have been made in other autoimmune diseases such as type 1 diabetes mellitus or systemic lupus erythematosus. Because of those findings, VD supplementation has been considered as a potential treatment, but further well-organized studies and larger randomized trials are necessary in order to confirm the potential of VD to prevent and ameliorate symptomatology in autoimmune diseases [11, 13].

Advertisement

5. Vitamin D deficiency and infectious diseases

Cathelicidin (in the form of LL-37), human beta-defensin 2, and perhaps the generation of reactive oxygen species could account for the antiviral properties of vitamin D. A recent study revealed that vitamin D-induced oxidative stress might be a mediator of the reduction in hepatitis C replication in human hepatoma cells. Given the pleiotropic effects of vitamin D, additional pathways may be present [14].

Because of its capacity to damage bacterial membranes via electrostatic interactions, LL-37 has an antibacterial effect [15]. Similar interactions might take place with virus lipid envelopes. Like how other antimicrobial peptides work, LL-37 may also prevent viral entrance [16]. Numerous investigations using enveloped viruses are included in the epidemiologic evidence demonstrating a favorable immunological impact connected to vitamin D. This bolsters the theory that envelope disruption may play a role in the antiviral actions of LL-37 [17].

5.1 Viral infectious

5.1.1 Viral respiratory infections

Recent research emphasizes the potential benefit of vitamin D in the treatment of viral respiratory infections. High baseline levels of CYP27B1 are expressed, while minimal levels of CYP24A are also expressed by lung epithelial cells, favoring the conversion of vitamin D into its active form [18]. These cells raise the expression of the TLR co-receptor CD-14 and cathelicidin when given vitamin D [19]. Treatment with vitamin D causes the NF-kB inhibitor IkB, which reduces the viral activation of inflammatory genes in airway epithelial cells [20].

By analyzing VDR polymorphisms, studies have discovered potential connections between vitamin D and respiratory diseases. Due to the relationship of the VDR gene with innate immunity, single-nucleotide polymorphisms in the VDR and related genes are linked to severe outcomes in infections of the lower respiratory tract (RTI) and bronchiolitis caused by the respiratory syncytial virus (RSV) [21, 22].

5.1.2 HIV infections

Vitamin D levels in HIV populations have been found to be lower in observational studies. In a German investigation, 25(OH)D concentrations less than 20 ng/ml (50 nmol/l) were discovered in 47.6% of the people with HIV [23].

Only 17% of participants in a study of HIV-positive adults from the United States had serum levels of 25(OH)D below normal levels, and only 11% had low levels of 1,25(OH)2D. However, the differences were statistically insignificant [24]. Additionally, 53 patients in Norwegian research had serum 1,25(OH)2D levels that were considerably lower than the controls [25].

5.1.3 Epstein: Barr virus infections

Multiple sclerosis (MS) and the Epstein–Barr virus (EBV) may be related, according to studies; as a result, vitamin D levels may be important in the emergence of MS [26, 27]. In Medical Hypotheses, Trygve Holmoy examined this subject. According to Holmoy, low vitamin D levels and EBV infection increase the incidence of MS. He suggests that vitamin D modifies the immunological response to EBV and inhibits the activation of auto-reactive T cells, which may be a contributing factor in the pathogenesis of MS [28].

5.1.4 HCV infections

Hepatocytes infected with the hepatotropic, single-stranded RNA virus known as HCV are the hallmark of the inflammatory liver condition known as hepatitis C. Worldwide it is estimated that 170 million people have HCV [29].

One of the most prevalent symptoms of HCV in clinical settings was VD deficit (plasma 25(OH)D3 20 ng/mL), and it was commonly noted that there was a negative association between VD levels and viral loads in HCV patients [30, 31]. Therefore, VD insufficiency has been identified as a risk factor for HCV infection and subsequent chronic progression [32]. In agreement with this finding, HCV patients’ plasma VD levels and the expression of the VDR were found to be negatively correlated [33].

5.1.5 HBV infections

Epidemiological studies consistently show considerably reduced VD levels in chronic HBV individuals [34]. The clinical development of liver cirrhosis and unfavorable clinical outcomes was linked to lower VD levels [35]. This clinical evidence was supported by the finding that HBV transcription and translation were increased in HBV-transfected cells when VDR expression was downregulated [36]. Contrarily, in HBV patients receiving effective antiviral medication, VD levels returned to normal [37].

5.2 Bacterial infections

5.2.1 Streptococcal infections

For many years, vitamin D has been known to have chemotherapeutic potential in the treatment of bacterial infections [38]. Vitamin D has been demonstrated to have immunomodulatory effects within the host, possibly preventing bacterial growth and biofilm formation. But studies have also demonstrated that vitamin D has direct antibacterial and antibiofilm activity against a few organisms, including streptococci. Streptococcus pyogenes, Escherichia coli, and Klebsiella pneumonia all showed substantial growth suppression in vitro, according to research [39].

Recent studies have shown that vitamin D analogs cause the planktonic cultures of Streptococcus mutans to lyse and impede the production of biofilms, which is essential for complete pathogenicity. Alfacalcidol, calcitriol, and doxercalciferol were found to cause S. mutans planktonic cells to lyse at least two times more frequently than DMSO, according to Saputo et al. The only compounds that prevented the development of biofilms were calcitriol and doxercalciferol, with calcitriol having a 40-fold stronger inhibitory effect than DMSO. In the same publication, it was also shown that doxercalciferol reduced the minimum inhibitory concentration (MIC) of bacitracin from 128 to 4 g/mL, sensitizing bacitracin-resistant S. mutans to the drug [40].

Increased risk of infection is linked to vitamin D deficiency, and supplementing changes how hosts and pathogens interact. Deficiencies in micronutrients, such as inadequate vitamin D levels, have been linked to a higher risk of illness, particularly infections brought on by Streptococcus [41, 42]. The risk of tonsillopharyngitis and community-acquired streptococcal pneumonia has specifically been linked to vitamin D deficiency [41].

A retrospective analysis of 54 individuals with tonsillopharyngitis brought on by GAS revealed that the condition was linked to a serum concentration of vitamin D (25(OH)D) less than 20 ng/mL [43]. These findings support a previous study that discovered men with 25(OH)D blood levels below 40 nmol/L had more severe infections of the respiratory tract [43, 44].

Vitamin D administration has also been demonstrated to increase neutrophil killing of infectious streptococcal bacteria while concurrently reducing severe inflammatory responses and apoptosis, suggesting vitamin D may have anti-streptococcal effects [45].

5.2.2 Mycobacterium tuberculosis infections

In vivo mycobacterium TB infections were shown to be resistant to vitamin D supplementation in early investigations [46]. The antimicrobial peptide cathelicidin is induced by TLR activation and promotes the intracellular mortality of M. tuberculosis in human monocytes and macrophages by causing the expression of the vitamin D receptor and vitamin D-1 hydroxylase genes [47]. When vitamin D was applied topically to M. tuberculosis cultures in the form of oil or propylene glycol, it was seen that the number of tubercle bacilli decreased over the course of days to weeks. M. tuberculosis was also unable to develop on a medium that had vitamin D added to it. Interestingly, tuberculosis was treated with codfish oil in Europe in the 1700s before its bactericidal effect was recognized. Codfish oil is a well-known source of vitamin D [48].

Numerous studies have questioned the relationship between vitamin D levels and the likelihood of developing active TB in patients exposed to MT, given the characteristics and mechanisms of action of vitamin D now understood. In patients with active TB, there is a lower level of 25(OH)D than in healthy individuals, according to research [49, 50, 51]. Uncertainty exists regarding the relationship between the vitamin D shortage and infection, as well as whether the vitamin D deficiency favors the infection’s progression. The capacity of vitamin D to prevent the replication of MT in vitro has also been demonstrated [51]. For instance, research has demonstrated that cholecalciferol concentrations as low as 4 ng/mL are adequate to inhibit the growth of the bacillus inside produced human macrophages. This number is substantially greater than the amounts of 1,25(OH)2D that are normally seen in the blood, but since infected macrophages can produce this active form of vitamin D on their own, it is possible that they may achieve such levels [52].

5.3 Fungal infections

Beyond its well-established functions, recent research suggests that vitamin D also has a connection with susceptibility to and management of fungal infections. Fungal infections can be caused by various fungi present in our environment. While most fungi are harmless, a few types can cause diseases, particularly in individuals with compromised immune systems. The body’s ability to resist these infections is heavily dependent on a well-functioning immune system, and this is where the potential link with vitamin D emerges. Vitamin D is known to modulate the immune system, affecting both innate and adaptive immune responses. Its active form, calcitriol, has been shown to stimulate the production of antimicrobial peptides, which are critical in the defense against fungal pathogens [53].

The relationship between vitamin D and fungal infections has been particularly explored in the context of Candida infections. Candida is a type of yeast that lives on the skin and inside the body. While generally harmless, it can cause infections if the body’s natural balance is disrupted, or the immune system is weakened. Several studies have found that individuals with recurrent or severe Candida infections often have low levels of vitamin D, suggesting that this vitamin might play a protective role.

Furthermore, in vitro studies have demonstrated that vitamin D can inhibit the growth of Candida by promoting the production of certain antimicrobial peptides. In these studies, cells treated with calcitriol produced higher amounts of these peptides, leading to decreased growth of the fungus. This gives credence to the idea that vitamin D supplementation could serve as an adjunct treatment for Candida infections [45].

The correlation between vitamin D and Aspergillus infections is another area of interest. Aspergillus is a common fungus that can cause serious lung infections in people with weakened immune systems. In animal models, vitamin D deficiency has been linked to a higher susceptibility to Aspergillus infections. Moreover, supplementation with vitamin D has been found to enhance the ability of immune cells to kill Aspergillus, providing further evidence of its potential therapeutic role.

However, while these findings are promising, it is important to note that much of the research on vitamin D and fungal infections is still in the preliminary stages. Many of the studies have been conducted in vitro or in animal models, and human trials are needed to confirm these results. Additionally, while vitamin D deficiency can increase susceptibility to infections, excessive intake is not without risks. Vitamin D is a fat-soluble vitamin, meaning it can build up in the body to toxic levels if consumed in large amounts.

The rising prevalence of candidiasis infections presents a significant threat to public health, given its high morbidity and mortality rates. This critical situation is further exacerbated by the current limitations of antifungal drugs available in the market. Consequently, there has been an increasing interest in the development of novel, more effective antifungal agents to manage and reduce the burden of candida. This study focuses on the potential of vitamin D3 (VD3) as a viable candidate in this regard, especially given its potent antifungal activity against various Candida species.

One study employed both the broth microdilution method and solid plate assay to investigate the antifungal properties of VD3 [54]. The results confirmed that VD3 inhibited the growth of Candida species in a broad-spectrum, dose-dependent manner. This implies that increasing concentrations of VD3 have a stronger inhibitory effect on Candida species, thereby enhancing its potential as an effective antifungal agent [45, 53].

Furthermore, studies reveal that VD3 had a significant impact on the initiation, development, and maturation phases of biofilm formation in Candida albicans, a common cause of IAC. The suppression of biofilm formation is particularly significant as biofilms are often resistant to antifungal agents, and their formation plays a critical role in the persistence and severity of Candida infections.

The underlying mechanism through which VD3 exerts its antifungal effects was further explored using transcriptomics and reverse transcription quantitative PCR (RT-qPCR) analysis. Findings from these analyses revealed that VD3 influences several key biological processes, including ribosome biogenesis, coenzyme metabolism, and carbon metabolism. This suggests that VD3’s antifungal activity against C. albicans may be attributed to its multitarget effects, disrupting various essential metabolic processes [54].

In a murine IAC model, VD3 demonstrated significant efficacy in reducing the fungal burden in various organs, including the liver, kidneys, and small intestine. This points to the potential systemic benefits of VD3 in controlling and reducing the spread of fungal infections within the body, thereby further consolidating its promise as an antifungal agent.

In addition to its direct antifungal effects, the study also revealed that VD3 significantly reduced the infiltration of inflammatory cells, a common occurrence in IAC. This suggests that VD3 may also have potent anti-inflammatory properties that could aid in managing the symptoms and severity of IAC.

The impact of VD3 on plasma cytokine levels was also investigated. Results confirmed that VD3 treatment significantly decreased the levels of plasma interferon (IFN)-γ and tumor necrosis factor (TNF)-α, both of which are typically elevated in response to fungal infections. This suggests that VD3 may modulate the body’s immune response to fungal infections, further enhancing its potential as an antifungal agent [52].

The latest findings provide compelling evidence that VD3 may offer a novel antifungal mechanism with broad-spectrum activity against various Candida species. These results not only enhance our understanding of the antifungal properties of VD3 but also suggest its potential as a therapeutic agent in the treatment of IAC. Future studies should focus on assessing the safety and efficacy of VD3 in clinical settings, as well as exploring possible synergies with existing antifungal agents [45, 54].

5.4 Parasitic infection

In a recent study investigating the correlation between vitamin D levels and parasitic infections, findings indicated that individuals who tested positive for the Toxoplasma gondii IgG antibody, an indicator of a past or present infection with the T. gondiiparasite, had lower serum 25(OH)D levels, as serum 25(OH)D is a common measure of vitamin D status in the body. The study further found that vitamin D insufficiency was significantly associated with an increased risk of T. gondii infection, a correlation that remained robust even after adjustment for potential confounding factors [55].

Previous research on the association between vitamin D levels and T. gondii antibody seroprevalence has yielded mixed results. While some small-scale studies suggested that vitamin D deficiency increases the risk of T. gondii infection, a larger study disputed this hypothesis. In contrast, this study, which utilized a nationally representative dataset, found a strong association between vitamin D deficiency and the risk of T. gondii infection. The findings suggest that the effects of vitamin D status on T. gondii infection risk were independent of age and other potential confounders, thus strongly supporting the hypothesis that vitamin D levels may play a protective role against T. gondii infection [19, 55].

An inverse relationship between low vitamin D levels and high seroprevalence of parasitic antibodies could be explained by vitamin D deficiency impairing both the innate and adaptive immune responses. There is evidence to suggest that 1,25-dihydroxy vitamin D3, the active form of vitamin D, may inhibit intracellular T. gondii proliferation both in vivo and in vitro. However, whether vitamin D supplementation could offer protection against parasitic infection in humans has not yet been demonstrated, and further investigation is required [56].

It is also possible that factors confounding the estimation of the relationship between vitamin D levels and parasitic infections might explain the study’s results. For example, patients with metabolic syndromes often have lower vitamin D levels. For example, T. gondii exposure is also elevated in women with obesity and poor dietary quality. Therefore, an inadequate diet and higher metabolic risk might connect lower vitamin D levels to a higher risk of foodborne toxoplasmosis.

Despite the study’s thorough efforts to minimize the influence of confounders, several limitations were inevitable. Due to the cross-sectional nature of the study, it was not possible to establish a definitive causal relationship between low vitamin D levels and parasitic infections. However, to validate these hypotheses, further prospective studies would be necessary [55, 56].

Advertisement

6. Conclusions

In the latest years have been extended the knowledge about vitamin D and its implications regarding health. Because of the increasing number of people, both children and adults affected by vitamin D deficiency have recommended supplementation by dietary intake [57, 58].

Because VD has an important influence on the immune system and low levels of 25(OH)D are associated with high incidence and severity of different infectious diseases, VD supplementation should be considered, but further studies are necessary in order to confirm this hypothesis [59].

Advertisement

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. 1. Deluca HF. History of the discovery of vitamin D and its active metabolites. Bonekey Reports. 2014;3:479. DOI: 10.1038/bonekey.2013.213
  2. 2. Chang SW, Lee HC. Vitamin D and health - the missing vitamin in humans. Pediatrics and Neonatology. 2019;60(3):237-244. DOI: 10.1016/j.pedneo.2019.04.007
  3. 3. Capone K, Sentongo T. The ABCs of nutrient deficiencies and toxicities. Pediatric Annals. 2019;48(11):e434-e440. DOI: 10.3928/19382359-20191015-01
  4. 4. Beckett EL, Yates Z, Veysey M, Duesing K, Lucock M. The role of vitamins and minerals in modulating the expression of microRNA. Nutrition Research Reviews. 2014;27(1):94-106. DOI: 10.1017/S0954422414000043
  5. 5. López Plaza B, Bermejo López LM. Nutrición y trastornos del sistema inmune [Nutrition and immune system disorders]. Nutrición Hospitalaria. 2017;34(Suppl 4):68-71. Spanish. DOI: 10.20960/nh.1575
  6. 6. Nair R, Maseeh A. Vitamin D: The "sunshine" vitamin. Journal of Pharmacology and Pharmacotherapeutics. 2012;3(2):118-126. DOI: 10.4103/0976-500X.95506
  7. 7. Bendik I, Friedel A, et al. Vitamin D: A critical and essential micronutrient for human health. Frontiers in Physiology. 2014;5:248. DOI: 10.3389/fphys.2014.00248
  8. 8. Argano C, Mallaci Bocchio R, et al. Protective effect of vitamin D supplementation on COVID-19-related intensive care hospitalization and mortality: Definitive evidence from meta-analysis and trial sequential analysis. Pharmaceuticals (Basel). 2023;16(1):130. DOI: 10.3390/ph16010130
  9. 9. Tomaszewska A, Rustecka A, et al. The role of vitamin D in COVID-19 and the impact of pandemic restrictions on vitamin D blood content. Frontiers in Pharmacology. 2022;13:836738. DOI: 10.3389/fphar.2022.836738
  10. 10. Liu Z, Huang S, et al. The role of vitamin D deficiency in the development of paediatric diseases. Annals of Medicine. 2023;55(1):127-135. DOI: 10.1080/07853890.2022.2154381
  11. 11. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chemistry & Biology. 2014;21(3):319-329. DOI: 10.1016/j.chembiol.2013.12.016
  12. 12. Gois PHF, Ferreira D, Olenski S, Seguro AC. Vitamin D and infectious diseases: Simple bystander or contributing factor? Nutrients. 2017;9(7):651. DOI: 10.3390/nu9070651
  13. 13. Yang CY, Leung PS, Adamopoulos IE, Gershwin ME. The implication of vitamin D and autoimmunity: A comprehensive review. Clinical Reviews in Allergy and Immunology. 2013;45(2):217-226. DOI: 10.1007/s12016-013-8361-3
  14. 14. Yano M, Ikeda M, et al. Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal-regulated kinase. Hepatology. 2009;50(3):678-688. DOI: 10.1002/hep.23026
  15. 15. Bals R, Wilson JM. Cathelicidins--a family of multifunctional antimicrobial peptides. Cellular and Molecular Life Sciences. 2003;60(4):711-720. DOI: 10.1007/s00018-003-2186-9
  16. 16. Leikina E, Delanoe-Ayari H, et al. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nature Immunology. 2005;6(10):995-1001. DOI: 10.1038/ni1248
  17. 17. Wang TT, Nestel FP, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. Journal of Immunology. 2004;173(5):2909-2912. DOI: 10.4049/jimmunol.173.5.2909
  18. 18. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense. Journal of Immunology. 2008;181(10):7090-7099. DOI: 10.4049/jimmunol.181.10.7090
  19. 19. Fakhrieh Kashan Z et al. Vitamin D deficiency and toxoplasma infection. Iranian Journal of Public Health. 2019;48(6):1184-1186
  20. 20. 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. Journal of Immunology. 2010;184(2):965-974. DOI: 10.4049/jimmunol.0902840
  21. 21. Janssen R, Bont L, et al. Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of Infectious Diseases. 2007;196(6):826-834. DOI: 10.1086/520886
  22. 22. Roth DE, Jones AB, et al. Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood. The Journal of Infectious Diseases. 2008;197(5):676-680. DOI: 10.1086/527488
  23. 23. Kuehn EW, Anders HJ, et al. Hypocalcaemia in HIV infection and AIDS. Journal of Internal Medicine. 1999;245(1):69-73. DOI: 10.1046/j.1365-2796.1999.00407.x
  24. 24. Coodley GO, Coodley MK, Nelson HD, Loveless MO. Micronutrient concentrations in the HIV wasting syndrome. AIDS. 1993;7(12):1595-1600. DOI: 10.1097/00002030-199312000-00008
  25. 25. Haug C, Müller F, Aukrust P, Frøland SS. Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: Correlation with degree of immune deficiency and survival. The Journal of Infectious Diseases. 1994;169(4):889-893. DOI: 10.1093/infdis/169.4.889
  26. 26. Levin LI, Munger KL, et al. Multiple sclerosis and Epstein-Barr virus. Journal of the American Medical Association. 2003;289(12):1533-1536. DOI: 10.1001/jama.289.12.1533
  27. 27. Haahr S, Höllsberg P. Multiple sclerosis is linked to Epstein-Barr virus infection. Reviews in Medical Virology. 2006;16(5):297-310. DOI: 10.1002/rmv.503
  28. 28. Holmøy T. Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis. Medical Hypotheses. 2008;70(1):66-69. DOI: 10.1016/j.mehy.2007.04.030
  29. 29. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. The Lancet Infectious Diseases. 2005;5(9):558-567. DOI: 10.1016/S1473-3099(05)70216-4
  30. 30. El Husseiny NM, Fahmy HM, Mohamed WA, Amin HH. Relationship between vitamin D and IL-23, IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians. World Journal of Hepatology. 2012;4(8):242-247. DOI: 10.4254/wjh.v4.i8.242
  31. 31. Schaalan MF, Mohamed WA, Amin HH. Vitamin D deficiency: Correlation to interleukin-17, interleukin-23 and PIIINP in hepatitis C virus genotype 4. World Journal of Gastroenterology. 2012;18(28):3738-3744. DOI: 10.3748/wjg.v18.i28.3738
  32. 32. Wu M, Yue M, et al. Vitamin D level and vitamin D receptor genetic variations contribute to HCV infection susceptibility and chronicity in a Chinese population. Infection, Genetics and Evolution. 2016;41:146-152. DOI: 10.1016/j.meegid.2016.03.032
  33. 33. Abdel-Mohsen MA, El-Braky AA, Ghazal AAE, Shamseya MM. Autophagy, apoptosis, vitamin D, and vitamin D receptor in hepatocellular carcinoma associated with hepatitis C virus. Medicine (Baltimore). 2018;97(12):e0172. DOI: 10.1097/MD.0000000000010172
  34. 34. Hu YC, Wang WW, et al. Low vitamin D levels are associated with high viral loads in patients with chronic hepatitis B: A systematic review and meta-analysis. BMC Gastroenterology. 2019;19(1):84. DOI: 10.1186/s12876-019-1004-2
  35. 35. Hoan NX, Khuyen N, et al. Association of vitamin D deficiency with hepatitis B virus - related liver diseases. BMC Infectious Diseases. 2016;16(1):507. DOI: 10.1186/s12879-016-1836-0
  36. 36. Gotlieb N, Tachlytski I, et al. Hepatitis B virus downregulates vitamin D receptor levels in hepatoma cell lines, thereby preventing vitamin D-dependent inhibition of viral transcription and production. Molecular Medicine. 2018;24(1):53. DOI: 10.1186/s10020-018-0055-0
  37. 37. Chen EQ, Bai L, et al. Sustained suppression of viral replication in improving vitamin D serum concentrations in patients with chronic hepatitis B. Scientific Reports. 2015;5:15441. DOI: 10.1038/srep15441
  38. 38. Eigenbrod T, Pelka K, et al. TLR8 senses bacterial RNA in human monocytes and plays a nonredundant role for recognition of streptococcus pyogenes. Journal of Immunology. 2015;195(3):1092-1099. DOI: 10.4049/jimmunol.1403173
  39. 39. Feindt E, Ströder J. Zur antimikrobiellen Wirkung von vitamin D [studies on the antimicrobial effect of vitamin D (author's transl)]. Klinische Wochenschrift. 1977;55(10):507-508. German. DOI: 10.1007/BF01489010
  40. 40. Saputo S, Faustoferri RC, Quivey RG Jr. Vitamin D compounds are bactericidal against Streptococcus mutans and target the bacitracin-associated efflux system. Antimicrobial Agents and Chemotherapy. 2017;62(1):e01675-e01617. DOI: 10.1128/AAC.01675-17
  41. 41. Pletz MW, Terkamp C, et al. D deficiency in community-acquired pneumonia: Low levels of 1,25(OH)2 D are associated with disease severity. Respiratory Research. 2014;15(1):53. DOI: 10.1186/1465-9921-15-53
  42. 42. Van Winden KR, Bearden A, et al. Low bioactive vitamin D is associated with pregnancy-induced hypertension in a cohort of pregnant HIV-infected women sampled over a 23-year period. American Journal of Perinatology. 2020;37(14):1446-1454. DOI: 10.1055/s-0039-1694007
  43. 43. Nseir W, Mograbi J, et al. The association between vitamin D levels and recurrent group a streptococcal tonsillopharyngitis in adults. International Journal of Infectious Diseases. 2012;16(10):e735-e738. DOI: 10.1016/j.ijid.2012.05.1036
  44. 44. Laaksi I, Ruohola JP, et al. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. The American Journal of Clinical Nutrition. 2007;86(3):714-717. DOI: 10.1093/ajcn/86.3.714
  45. 45. Lim JH, Ravikumar S, et al. Bimodal influence of vitamin D in host response to systemic Candida infection-vitamin D dose matters. The Journal of Infectious Diseases. 2015;212(4):635-644. DOI: 10.1093/infdis/jiv033
  46. 46. Raab W. Tuberculous empyema treated with vitamin A-D concentrate, a preliminary report. Diseases of the Chest. 1946;12:68-71. DOI: 10.1378/chest.12.1.68
  47. 47. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-1773. DOI: 10.1126/science.1123933
  48. 48. Guy RA. The history of cod liver oil as a remedy. American Journal of Diseases of Children. 1923;26(2):112-116. DOI: 10.1001/archpedi.1923.04120140011002
  49. 49. Elsafi SSMS, Nour BM, Abakar AD, Omer IH, Almugadam BS. Vitamin D level and it is association with the severity of pulmonary tuberculosis in patients attended to Kosti teaching hospital, Sudan. AIMS Microbiol. 2020;6(1):65-74. DOI: 10.3934/microbiol.2020004
  50. 50. Huang SJ, Wang XH, et al. Vitamin D deficiency and the risk of tuberculosis: A meta-analysis. Drug Design, Development and Therapy. 2016;11:91-102. DOI: 10.2147/DDDT.S79870
  51. 51. Venturini E, Facchini L, et al. Vitamin D and tuberculosis: A multicenter study in children. BMC Infectious Diseases. 2014;14:652. DOI: 10.1186/s12879-014-0652-7
  52. 52. Crowle AJ, Ross EJ, May MH. Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infection and Immunity. 1987;55(12):2945-2950. DOI: 10.1128/iai.55.12.2945-2950.1987
  53. 53. Romani L. Immunity to fungal infections. Nature Reviews. Immunology. 2011;11(4):275-288. DOI: 10.1038/nri2939
  54. 54. Lei J, Xiao W, Zhang J, et al. Antifungal activity of vitamin D3 against Candida albicans in vitro and in vivo. Microbiological Research. 2022;265:127200. DOI: 10.1016/j.micres.2022.127200
  55. 55. Tayeb F, Salman Y, Ameen K. The impact of toxoplasma gondii infection on the vitamin D3 levels among women in childbearing age in Kirkuk Province-Iraq. Open Journal of Medical Microbiology. 2019;9:151-167. DOI: 10.4236/ojmm.2019.94015
  56. 56. Kankova S, Bicikova M, et al. Latent toxoplasmosis and vitamin D concentration in humans: Three observational studies. Folia Parasitologica (Praha). 2021;68:1-7. DOI: 10.14411/fp.2021.005
  57. 57. Allegra A, Tonacci A, et al. Vitamin deficiency as risk factor for SARS-CoV-2 infection: Correlation with susceptibility and prognosis. European Review for Medical and Pharmacological Sciences. 2020;24(18):9721-9738. DOI: 10.26355/eurrev_202009_23064
  58. 58. Beheshti M, Neisi N, et al. Correlation of vitamin D levels with serum parameters in Covid-19 patients. Clinical Nutrition ESPEN. 2023;55:325-331. DOI: 10.1016/j.clnesp.2023.04.012
  59. 59. Suardi C, Cazzaniga E, Graci S, Dongo D, Palestini P. Link between viral infections, immune system, inflammation and diet. International Journal of Environmental Research and Public Health. 2021;18(5):2455. DOI: 10.3390/ijerph18052455

Written By

Larisa M. Marusca, Flavia A.E. Szekely, Delia I. Horhat and Florin G. Horhat

Submitted: 22 May 2023 Reviewed: 02 June 2023 Published: 11 June 2025