In this 2-part blog series, you’ll get a deep dive into the relationship between COVID-19 and Vitamin D, with recommendations on how you can apply these learnings to your clinical practice. Read on to discover the impact of Vitamin D on innate and adaptive immunity.
The association between Vitamin D levels and COVID-19 health outcomes
In December 2020, over 120 health scientists and medical experts from the UK, US, and Europe sent a COVID-19 open letter to their governments about a molecule that could help reduce COVID-19 related deaths and hospitalisation rates.  In that letter they talked about Vitamin D.
The recent scientific research conducted in various European countries showed an indisputable association between Vitamin D levels and COVID-19 associated cases and mortality rate.  A negative correlation had been observed between levels of mean Vitamin D (average 56.79 nmol/L) and number of COVID-19/1 M cases and COVID-19/1 M deaths. The figure bellow illustrates such findings. 
It is important to mention that in recent years, Vitamin D deficiency has become a major worldwide public health problem in all age groups, independently of latitude, or access to Vitamin D fortified foods. 
What is Vitamin D and why is it so important for our health?
Vitamin D was discovered about 100 years ago in Great Britain by Dr Edward Mellanby. At that time Rickets was highly prevalent in Scotland, so he decided to find the root cause of the disease.
Sir Mellanby conducted a dietary experiment on his dog, that was supposed to mimic the Scottish diet. During that experiment he fed his dog an oat-rich diet and kept it indoors away from sunlight. This is when he discovered a phenotype in dogs that was identical to Rickets in humans.  Sir Mellanby found that administration of cod liver oil helped cure the disease, however his final assumption was incorrect. He suggested that the curative component was vitamin A, when in fact, it was Vitamin D (A.K.A “The Sunshine Vitamin”), which was confirmed by McCollum and colleagues soon after. 
The 3 stages of endocrine Vitamin D production:  
- Cholecalciferol (Vitamin D) is a steroid hormone and one of the most common forms of Vitamin D groups. It is synthesized in the skin after exposure to sunlight (UVB light). This happens through a photosynthetic reaction where 7-dehydrocholesterol in the epidermis is converted to Cholecalciferol. *This stage is HAL enzyme dependent, because in the epidermis this enzyme acts like an internal sunblock, and diminishes the impact of UVB on the skin, which can indeed impact the first conversion.
- Then, Cholecalciferol gets picked up by Vitamin D Binding Protein (VDBP) and travels in the blood to the liver where it undergoes an enzymatic reaction and becomes a 25-hydroxyvitamin D (25(OH)D), or Calcidiol. 25(OH)D is referred as pro-hormone, and it is not yet in its bioavailable state. *This stage requires functionating enzyme CYP2R1, which is Magnesium dependent.
- Next, Calcidiol gets transported to the kidneys by VDBP again, where it completes its biotransformation into its final hormonal state – 1,25-dihydroxyvitamin D (1,25(OH)2D), or Calcitriol, which is the only biologically active form of hormone Vitamin D. *This stage requires functionating enzyme CYP27B1, which is also Magnesium dependent.
The next stage in Vitamin D’s biological journey: binding to Vitamin D receptors (VDR)
Calcitriol is transferred to the cells that have Vitamin D receptors (VDR). Calcitriol can initiate the physiologic responses of ≥36 cell types that possess the VDR.  Once the hormonal receptor (nVDR) is activated by Vitamin D in the nucleus, it becomes a gene transcriptional regulator. VDR then couples with Retinoid-X Receptor (RXR), which creates a heterodimer – a VDR transcription factor which then binds to our genes or VDBE (Vitamin D binding elements in target genes) and elicits gene expression.
Through VDR, Vitamin D can upregulate or downregulate over 3,000 genes involved in mineral metabolism and in non-calcemic functions, including innate and adaptive immunity.
The importance of Vitamin D receptors (VDR) in summary
- When VDR is not active – unbound to 1,25(OH)2D and un-complexed with RXR, the VDR suppresses gene expression in target genes, that have Vitamin D receptor binding regions.
- When VDR is active (bound to 1,25(OH)2D) it activates the VDR/RXR heterodimer as well as additional cell-type specific transcriptional regulators and induces gene expression.
- The highest VDR expression is found in such metabolic tissues as:
- Thyroid gland
- VDR modulates such biological processes as:
- Calcium and Phosphorus homeostasis
- Cell proliferation, differentiation, and apoptosis
- Immune response
What you need to know about Vitamin D autocrine metabolism
When 25(OH)D, or Calcidiol, is being circulated in the blood, it gets taken up by a wide variety of cells that contain both the CYP27B1 enzyme as well as nuclear Vitamin D receptors (nVDR). Such cells are capable of making their own Calcitriol rather than only relying upon hematogenous supply.  Cells and tissues that contain CYP27B1 enzyme include the breast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, and brain (cerebellum and cerebral cortex).  Cells and tissues with nuclear, cytosolic, or membrane-bound VDR include islet cells of the pancreas, monocytes, transformed B-cells, activated T-cells, neurons, prostate cells, ovarian cells, pituitary cells, and aortic endothelial cells.
With such a wide variety of cells and tissues metabolising Vitamin D in an autocrine manner, it becomes clear that Vitamin D plays an especially important role in the function and pathophysiology of multiple metabolic processes and disease states in the body.
Classical and nonclassical effect of Vitamin D. 
Increases Calcium and Phosphorus uptake in the intestine.
Upregulates osteoclast maturation for bone remodeling, induces FGF-23 production, promotes Calcium deposition in bone, and induces bone release in hypocalcemia.
Inhibits PTH synthesis and secretion. Keeping PTH levels balanced is paramount for good health, because high PTH levels are associated with increased risk for such conditions as myocardial infarction, stroke, and hypertension. The state of Vitamin D, and thus Calcium, deficiency elevates PTH levels which increases intracellular Calcium and may lead to cellular dysfunction that can contribute to the development of diabetes mellitus, neurologic diseases, malignancy, and degenerative joint disease. 
Has antiproteinuric effect, decreases Magnesium absorption, stimulates Calcium and Phosphate absorption, suppresses RAA system, increases nephron expression, decreases NF-kB activation.
Inhibits RAA system, suppresses ANP, inhibits smooth muscle cells proliferation, decreases the risk of hypertension and cardiovascular disease.
- Immune system
Stimulates innate immune system by inhibition of TH1 cells and promotion of TH2 cells; represses INF, IL-2, and GMCSF.
Increases insulin secretion and sensitivity, and expression of insulin receptor; Increases glucose uptake.
Regulates apoptosis and antitumor activity.
In this segment of our 2-part series on the role of Vitamin D, we have explored the crucial role that the “Sunshine Vitamin” plays within the body and the many systems it impacts; from immunity to bone health. Join us next week for the second installment in this series, where we’ll be sharing everything you need to know about Vitamin D in your clinical practice.