Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood

doi:10.1016/j.clinthera.2017.04.004

Clinical Therapeutics

Volume 39, Issue 5, May 2017, Pages 930-945

https://doi.org/10.1016/j.clinthera.2017.04.004 Get rights and content

Abstract

Purpose

Vitamin D is increasingly thought to play a role in regulating immunity. This comprehensive review updates the current understanding regarding ways in which we believe that vitamin D regulates responsiveness of the immune system and how serum status modulates the host defense against pathogens.

Methods

The literature was searched by using PubMed and Scopus with the following key words: vitamin D, immunity, innate and adaptive immunity, infectious disease, and vaccine response.

Findings

Vitamin D deficiency remains a major public health concern worldwide. The overall body of evidence confirms that vitamin D plays an important role in modulating the immune response to infections. Epidemiologic studies suggest a clear association between vitamin D deficiency and susceptibility to various pathogens. However, translation of vitamin D use into the clinic as a means of controlling infections is fraught with methodologic and epidemiologic challenges. The recent discovery of alternative activation pathways, different active forms of vitamin D, and possible interaction with non–vitamin D receptors provide further complications to an already complex interaction between vitamin D and the immune system. Moreover, it has become apparent that the individual responsiveness to supplementation is more dynamic than presumed from the static assessment of 25-hydroxy vitamin D status. Furthermore, the epigenetic response at the level of the individual to environmental changes and lifestyle or health conditions provides greater variation than those resulting from vitamin D receptor polymorphisms.

Implications

To understand the future of vitamin D with respect to clinical applications in the prevention and better control of infectious diseases, it is necessary to determine all aspects of vitamin D metabolism, as well as the mechanisms by which active forms interact with the immune system globally. For the most part, we are unable to identify tissue-specific applications of supplementation except for those subjects at high risk of osteomalacia and osteoporosis.

Introduction

Vitamin D is an essential dietary component for which biological effects occur only as a consequence of its metabolism into a family of daughter metabolites. Two of these are important for human health, vitamin D₂ (which is synthesized in plants and fungi) and vitamin D₃ (which is made in skin exposed to sunlight).¹ This fat-soluble molecule is biologically inert in humans and needs to be activated by 2 successive hydroxylations at positions 25 and 1 via reactions of the cytochrome P450 (CYP) enzymes CYP2R1 and CYP27B1, respectively (Figure 1). These components are hydroxylated primarily in the liver to form the main circulating form, 25-hydroxy vitamin D (25[OH]VitD), and then by the kidney or cells expressing the vitamin D–activating enzyme CYP27B1. The final active metabolite 1α,25-dihydroxy vitamin D (1α,25[OH]₂VitD) is able to interact with the cognate nuclear vitamin D receptor (VDR) at the target organ levels, which generates appropriate biological responses.²

The classic actions of vitamin D are control of bone remodeling and skeletal homeostasis.¹ However, the VDR gene is expressed in ~400 tissues and cell types, suggesting that vitamin D has a far wider physiologic function beyond the exclusive control of calcium metabolism. Upon activation, the VDR binds to hormone response elements on DNA sequences, resulting in expression or transrepression of specific gene products.³ Downstream targets of this nuclear receptor are involved in mineral metabolism but also in a variety of other metabolic pathways. Activated VDR modulates the transcription of many genes, and their downstream products regulate potent cell growth and differentiation effects.⁴

Parallel to the classic activation pathway, alternate routes have recently been described. They are initiated by CYP11A1 leading to different hydroxy metabolites, among which are 20(OH)VitD and 22(OH)VitD. They also exert pleiotropic effects.⁵ Furthermore, the well-established mechanism of activation by binding of 1α,25(OH)₂VitD to the genomic site of VDR coexists with nongenomic membrane-associated sites. In addition to the classic activation pathway, the VDR contains an alternative form binding-A-pocket, the occupation of which leads to rapid nongenomic responses at membrane level. There is also a membrane-associated rapid steroid-binding protein (also known as protein disulfide-isomerase A3) that has been identify also as an alternative membrane-bound receptor.⁶ Other nuclear receptor targets comprise the retinoic acid–related orphan receptors (ROR)α and RORγ, which also regulate some phenotype functions (particularly in skin cancer). Recently, 1β,25(OH)₂VitD has also been measured in human serum, which is a poor genomic agonist but a potent nongenomic antagonist of 1α,25(OH)₂VitD.⁷ Its exact role in health requires further exploration.

The potential role of vitamin D in modulating the host defense to foreign antigens and pathogens has been investigated and some VDR transcription-dependent actions identified as having a role in regulating the immune system.8, 9 However, the exact roles played by the different bioactive forms via VDR and non-VDR receptors remains to be identified.⁵ More recently, the VDR network has been extended outside the immune system,¹⁰ with studies showing that intestinal VDR was associated with maintaining the gut intestinal barrier and regulating intestinal inflammation, autophagy, and susceptibility to infection.11, 12 Moreover, intestinal VDR was shown to be regulated by vitamin D and also by the gut microbiota and other hormonal compounds.¹⁰

The goal of the present comprehensive review was to highlight the current body of evidence on ways by which vitamin D status interferes with the normal responsiveness in the immune system. How serum vitamin D status acts on the host defense against infections, both positively and negatively, and the clinical perspectives in terms of vitamin D supplementation for the treatment and prevention of infectious diseases are also discussed.

Section snippets

Vitamin D–Mediated Therapies for Infections: More Than a Century of Evidence

Vitamin D–mediated remedies for infectious disorders have been suggested for more than a century. In 1903, the Nobel Prize of medicine was awarded to Niels Ryberg Finsen, who demonstrated that ultraviolet (UV) light was beneficial in treating lupus vulgaris, a skin disorder associated with Mycobacterium tuberculosis.¹³ Subsequently, the use of cod liver oil was widely practiced in the late 19th and 20th centuries and resulted in a steady decline in death rates from tuberculosis in the United

How does the Immune System work?

The immune system comprises 2 distinct but interacting types of immunity: innate and adaptive. In the frame of infectious diseases, the purpose of the immune system is to recognize invading pathogens, prevent their spread, and eliminate them from the body.¹ This extraordinarily complex system relies on billions of cells patrolling the body and a dynamic complex network of soluble mediators. The innate immunity is our body’s first line of defense that responds to foreign antigens in a generic

Vitamin D and the Immune System

The immunomodulatory role of vitamin D mediated via 25(OH)VitD and 1α,25(OH)₂VitD has been extensively reviewed previously.¹³ Much of the current knowledge has arisen from studies using animal models and ex vivo human cells and exposure to exogenous 1α,25(OH)₂VitD at amounts usually much higher than physiologic levels.¹³ The results showed that the activity of both innate (ie, monocytes, macrophages, dendritic cells) and B and T cells can be regulated by vitamin D (Figure 1) not only via the

Beyond Building Bone, What is the Optimal Serum Vitamin D Status for Immunity Health?

The circulating 25(OH)VitD concentration is often taken as the common correlate of vitamin D status and a true reflection of the vitamin D produced by the skin and obtained from food and/or supplements. This stable metabolite has a concentration that is 1000-fold higher than the active form and a circulating half-life of ~2 weeks. In contrast, circulating 1α,25(OH)₂VitD has a shorter half-life (~15 hours), and its serum concentrations are closely regulated by using parathyroid hormone, calcium,

Serum Vitamin D Concentration and Degree of Susceptibility to Infections

Epidemiologic studies have reinforced the hypothesis that vitamin D deficiency can profoundly mitigate our susceptibility to diverse pathogens. This action was first suspected when it was reported that the incidence of viral infections typically peaked during winter months when epidermal vitamin D synthesis was lower and serum 25(OH)VitD levels reached a nadir.¹⁴ It was then shown that children with inadequate serum levels experienced infections of viral origin, particularly influenza virus and

The Most Recent Data Tends Toward “Yes”...

A recent systematic review, whose aim was to consolidate data regarding the use of vitamin D as a treatment or preventive strategy against infections, considered 38 trials from 60 eligible articles and 1284 identified manuscripts.⁴⁴ Studies that considered analogue, topical, or micronutrient formulations of vitamin D, and assessed only serum status or lacked a comparison group, were excluded. Kearns et al concluded that although some prospective studies yield positive results, several robust

Vitamin D and Vaccine Response

In terms of prevention of infectious diseases, vaccines are the most powerful of public health tools. They provide tremendous benefits in protecting vulnerable populations against life-threatening and disabling pathogens worldwide.⁶⁷ In response to vaccines, the potential role played by vitamin D may be mediated via its direct interaction with antigen-presenting cells and more particularly with dendritic cells as specifically reviewed recently.² These roles may include dendritic cell

How to Optimize Vitamin D Status Efficiently and Safely

Production of vitamin D in the skin requires exposure to UVB-containing wavelengths (λ = 280–320 nm), and this action is expected to naturally supply the body’s requirement for this pro-hormone. Interestingly, vitamin D produced in the skin may last at least twice as long in the blood compared with ingested forms. The same spectrum of solar radiation, UVB, also represents a major risk factor for all forms of skin damage and cancers, including malignant melanoma.⁸⁰ During the photochemical

Is the Serum Value the Right Target?

In addition to the methodologic weaknesses previously emphasized to explain why clinical trials have failed to take advantage of vitamin D, the ways in which we chose to exert these immunomodulatory roles also plays a part in this acknowledgement of failure. Indeed, it is becoming increasingly clear that the dynamic response to vitamin D (ie, the individual responsiveness to vitamin D) does not correlate with the static assessment of the serum status. Some arguments to this statement are

Conclusions

The overall body of evidence suggests that vitamin D plays an important role in modulating the immune response to infection. Although the association between vitamin D deficiency and the susceptibility to various pathogens is becoming clearer, this review demonstrates that the achievement of an accurate assessment of the health benefits of optimized vitamin D status is still fraught with methodologic and epidemiologic challenges. Moreover, it becomes particularly clear that the dynamic

Conflicts of Interest

The authors have indicated that they have no conflicts of interest regarding the content of this article

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Steroid immune responsive gene regulation in Mycobacterium tuberculosis infection in vitro
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Tuberculosis (TB) is an infectious disease displaying a multifactorial pathology. The immunomodulatory role attributed to steroid hormones, such as vitamin D₃ (VD₃) and 17β-estradiol (E₂), highlighted the importance of these hormones against Mycobacterium tuberculosis (Mtb) infection. In order to understand their influence upon gene expression of immune and inflammatory responsive genes against Mtb we tested it in vitro using peripheral blood mononuclear cells (PBMCs). Cells were pretreated with VD₃ (50 ng/mL) or E₂ (100 nM/mL) and co-cultured with H37Rv Mtb or stimulated with lipopolysaccharide from Escherichia coli (LPS). After 24 h and 72 h of co-culture the Mtb viability in macrophages test was performed, as well the total RNA isolation for gene expression analysis by RT-qPCR of the following target genes: NLRP3, DC-SIGN, IL-1β, and IL-10. We also measured IL-10, TNF, IFN-γ, IL-4, IL-6, and IL-2 supernatant levels. As the main results, we found that VD₃ and E₂ downregulated the expression of inflammatory genes NLRP3, IL-1β, and IL-10 expression in Mtb co-cultured cells. Finally, VD₃ treatment increased the release of the cytokine IFN-γ in Mtb-infected cells, while E₂ treatment inhibited the release of IL-10, TNF, IFN-γ, and IL-6. Therefore, we report an immunogenetic influence of VD₃ and E₂ upon Mtb co-culture.
25-Hydroxyvitamin D concentrations do not affect the humoral or cellular immune response following SARS-CoV-2 mRNA vaccinations
2024, Vaccine
To improve effectiveness of vaccination against SARS-CoV-2, it is important to identify factors that influence the immune response induced by vaccination. Evidence for the role of vitamin D in immune response against SARS-CoV-2 is contradictory. It is therefore of interest whether 25-hydroxyvitamin D (25[OH]D) concentrations affect the humoral and/or cellular response following SARS-CoV-2 vaccination.
In this prospective cohort study, blood samples were collected from 98 SARS-CoV-2 naive health care workers (HCW) receiving the first two doses of either BNT162b2 or mRNA-1273 in 2021. Wild-type spike (S) protein binding and neutralizing antibodies were determined approximately three weeks after the first dose and four to five weeks after the second dose. Antigen specific T-cells and functionality (proliferative response and interferon gamma [IFN-γ] release) were determined in 18 participants four weeks after the second dose of BNT162b2. We studied the association between 25(OH)D concentrations, which were determined prior to vaccination, and humoral and cellular immune responses following vaccination.
We found no association between 25(OH)D concentrations (median 55.9 nmol/L [IQR 40.5–69.8]) and binding or neutralizing antibody titers after complete vaccination (fold change of antibody titers per 10 nmol/L 25(OH)D increase: 0.98 [95% CI 0.93–1.04] and 1.03 [95% CI: 0.96–1.11], respectively), adjusted for age, sex and type of mRNA vaccine. Subsequently, continuous 25(OH)D concentrations were divided into commonly used clinical categories (<25 nmol/L [n = 6, 6%], 25–49 nmol/L [n = 33, 34%], 50–75 nmol/L [n = 37, 38%] and ≥75 nmol/L [n = 22, 22%]), but no association with the humoral immune response following vaccination was found. Also, 25(OH)D concentrations were not associated with the SARS-CoV-2 specific T cell response.
No association was found between 25(OH)D concentrations and the humoral or cellular immune response following mRNA vaccination against SARS-CoV-2. Based on our findings there is no rationale to advise vitamin D optimization preceding SARS-CoV-2 vaccination in HCW with moderate vitamin D status.
Single nucleotide polymorphisms in genes involved in immune responses and outcome of tegumentary leishmaniasis
2022, Acta Tropica
Leishmaniases are neglected tropical diseases with a broad clinical spectrum. Tegumentary leishmaniasis (TL) is a disease caused by different Leishmania species, transmitted by phlebotomine sand flies and distributed worldwide. TL can present a cutaneous (CL) or mucocutaneous (MCL) clinical form depending on factors inherent to the parasite, the host and the vector. Polymorphisms in the immune response genes are host genetic factors that influence the pathogenesis or control of leishmaniasis. Single nucleotide polymorphisms (SNPs) in immune genes have been evaluated in several countries where leishmaniasis is endemic. In this review, we report studies on SNPs in several immune genes that might be associated with susceptibility or resistance to TL. We summarize studies from around the world and in Brazil, highlight the difficulties of these studies and future analyses needed to enhance our knowledge regarding host genetic factors in TL. Understanding the genetic characteristics of the host that facilitate resistance or susceptibility to leishmaniasis can contribute to the development of immunotherapy schedules for this disease. The current treatment methods are toxic, and no human vaccine is available.
Vitamin D and its' role in Parkinson's disease patients with SARS-CoV-2 infection. A review article
2022, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Citation Excerpt :
Fig. 1 Multiple recent reviews have shown some ways through which vitamin D reduces the risk of infections [24–27]. Vitamin D helps by three mechanisms to minimize the risk of common infections: physical barrier, cellular immunity, and adaptive immunity [28].
A novel coronavirus reportedly called 2019-nCoV started to spread around the world at the end of 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was later renamed after links with SARS were observed. Multiple studies have reported possible connections between the COVID-19 virus and neurodegenerative diseases, including Parkinson's disease. Theories support that vitamin D deficiency plays a part in the pathogenicity of Parkinson's disease or the credibility of the associated dopamine system. Administration of vitamin D3 was shown to significantly enhance the motor and non-motor manifestations of Parkinson's disease and enhance the quality of life. Also, multiple recent reviews have shown specific ways in which vitamin D reduces the risk of pathogenic infections. Recent studies supported the potential role of vitamin D in reducing the risk of COVID-19 infections and mortality. On the immunological level, immune response regulation remains one of the well-recognized actions of vitamin D. Vitamin D deficiency has been linked to complications in patients with SARS-CoV-2 infection and Parkinson's disease. Whereas more studies are required, Vitamin D supplementation with a moderate and well-calculated dosage of vitamin D3 in patients with Parkinson's disease can help minimize the risk and burden of COVID-19 complications.
Serum Calcium and Vitamin D levels: Correlation with severity of COVID-19 in hospitalized patients in Royal Hospital, Oman
2021, International Journal of Infectious Diseases
Studies have revealed hypocalcemia and low vitamin D levels in severe covid-19 that warrant further research.
Our study investigates the correlation between calcium levels at presentation as a primary endpoint and pre-existing calcium levels as a secondary endpoint to the severity of disease presentation and progression.
Observational cohort study in adults admitted with COVID-19 from March utill September 2020. Multiple clinical scales and laboratory parameters were used to correlate corrected calcium and vitamin D associations with risk factors and outcomes.
Four hundred and forty five patients were included in the study. Hypocalcemic patients had more abnormal laboratory parameters and longer hospitalization duration. Hypocalcemia was in 60–75% of all age groups (p-value 0.053), for which 77.97% were ICU admissions (p-value 0.001) and 67.02% were diabetic (p-value 0.347). There were non-significant correlations between Vitamin D and almost all the parameters except for chronic respiratory diseases, which had a P-value of 0.024.
It can be concluded that hypocalcemia is a significant and reliable marker of disease severity and progression regardless of underlying comorbidities. Vitamin D levels fail to reflect correlation with severity of COVID-19 infections.
Paracoccidioides brasiliensis induces IL-32 and is controlled by IL-15/IL-32/vitamin D pathway in vitro
2021, Microbial Pathogenesis
Citation Excerpt :
However, the consequences of these findings for the outcome of the disease have not been investigated. Vitamin D effects have been investigated in several infectious diseases, including virus, bacteria, protozoa and fungi, showing increase of macrophage microbicidal activity and immunomodulatory actions [24,63–66]. In this study, we have demonstrated, for the first time, that IL-32 is induced by P. brasiliensis, and that IL-15 and IL-32 activate the vitamin D pathway to increase the microbicidal activity against P. brasiliensis.
Paracoccidioidomycosis (PCM) is a systemic fungal disease caused by Paracoccidioides spp., whose clinical outcome depends on immune response. Interleukin 32 (IL-32) is a cytokine present in inflammatory and infectious diseases, including bacterial, virus and protozoan infections. Its role in fungal disease remains unclear. The axis IL-15, IL-32 and vitamin D leads to microbicidal capacity against intracellular pathogens. Thus, the aims of this study were to investigate the production of IL-32 during Paracoccidioides spp. infection and whether this cytokine and IL-15 can increase P. brasiliensis control in a vitamin D dependent manner. IL-32 was highly detected in oral lesions from patients with PCM. In addition, high production of this cytokine was intracellularly detected in peripheral blood mononuclear cells (PBMCs) from healthy donors after exposure to particulated P. brasiliensis antigens (PbAg). The IL-32 $γ$ isoform was predominantly expressed, but there was mRNA alternative splicing for IL-32α isoform. The induction of IL-32 was dependent on Dectin-1 receptor. Infection of PBMCs with P. brasiliensis yeasts did not significantly induce IL-32 production even after activation with exogenous IFN-γ or IL-15 treatments. Although IL-15 was a potent inducer of IL-32 production, treatment with this cytokine did not increase the fungal control unless vitamin D was present in high levels. In this case, both IL-15 and IL-32 increased fungicidal activity of PBMCs. Together, data showed that IL-32 is present in lesions of PCM, PbAg induces IL-32, and the axis of IL-15/IL-32/vitamin D can contribute to control fungal infection. The data suggest that exposure to molecules from P. brasiliensis, as β-glucans, is needed to induce IL-32 production since only heat-killed and sonicated P. brasiliensis yeasts were able to increase IL-32, which was blocked by anti-Dectin-1 antibodies. This is the first description about IL-15/IL-32/vitamin D pathway role in P. brasiliensis infection.

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CommentaryVitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood

Abstract

Purpose

Methods

Findings

Implications

Introduction

Section snippets

Vitamin D–Mediated Therapies for Infections: More Than a Century of Evidence

How does the Immune System work?

Vitamin D and the Immune System

Beyond Building Bone, What is the Optimal Serum Vitamin D Status for Immunity Health?

Serum Vitamin D Concentration and Degree of Susceptibility to Infections

The Most Recent Data Tends Toward “Yes”...

Vitamin D and Vaccine Response

How to Optimize Vitamin D Status Efficiently and Safely

Is the Serum Value the Right Target?

Conclusions

Conflicts of Interest

Chem Biol

J Steroid Biochem Mol Biol

Eur Geriatr Med

J Hepatol

Am J Med Sci

Am J Clin Nutr

J Steroid Biochem Mol Biol

Am J Clin Nutr

Lancet

Diabetes Metab Syndr

Endocrinol Met Clin N Am

Vaccine

J Nutr Health Aging

J Formos Med Assoc

Can we translate vitamin D immunomodulating effect on innate and adaptive immunity to vaccine response

The concept of the personnal vitamin D response index

J Steroid Biochem Mol Biol

The first gemone-wide view of vitamin D receptor locations and their mechanistic implications

Anticancer Res

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Lab Invest

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as "biased" agonists on VDR and inverse agonists on RORα and RORγ

J Steroid Biochem Mol Biol

1β,25-Dihydroxyvitamin D3: a new vitamin D metabolite in human serum

J Steroid Biochem Mol Biol

Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response

Physiol Rev

Vitamin D metabolism and signaling in the immune system

Rev Endocr Metab Disord

Role of vitamin D in the hygiene hypothesis: the interplay between vitamin D, vitamin D receptors, gut microbiota, and immune response

Front Immunol

Role of vitamin D on gut microbiota in cystic fibrosis

J Steroid Biochem Mol Biol

How important is vitamin D in preventing infections?

Osteoporos Int

The role of UV radiation and vitamin D in the seasonality and outcomes of infectious disease

Photochem Photobiol Sci

Vitamin D deficiency and the risk of tuberculosis: a meta-analysis

Drug Des Devel Ther

Vitamin D every day to keep the infection away?

Nutrients

Modulation of immune response by ultra-violet light in HLA class-II transgenic mice

Jacobs J Allergy Immunol

Effect of serum vitamin D levels on cellular immunity and antiviral effects in chronic hepatitis B patients

Clin Lab

Vitamin D in critically ill patients

Anaesthesiol Intensive Ther

Anti-inflammatory effects of vitamin D on human immune cells in the context of bacterial infection

Nutrients

Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study

J Transl Med

Vitamin D induces interleukin-1β expression: paracrine macrophage epithelial signaling controls M. tuberculosis infection

PLoS Pathog

Serum 25-hydroxyvitamin d level and influenza vaccine immunogenicity in children and adolescents

PLoS One

25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype

J Clin Endocrinol Metab

Optimal vitamin D supplementation strategies

Endocrine

Is there an optimal vitamin D status for immunity in athletes and military personnel?

Exerc Immunol Rev

Commentary
Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood