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ACADEMIA Letters Vitamin D Correlation to COVID-19 Nidhi Bhasin Introduction The COVID-19 disease caused by SARS-CoV-2 was declared as a pandemic by the World Health Organization (WHO)) on 11th March 2020. It spread all around the world infecting millions of people, causing a deep loss to life and livelihood. But since the beginning undying efforts to curb the situation had been going on, the development of safety protocols, public education towards infection prevention, development of vaccines and therapies, clinical and research based observations and experiments all have been aimed towards the eradication of this deadly disease. A huge number of clinical observations, research experiments and studies have discovered and established the importance of Vitamin D in the prevention and treatment of COVID-19, making it emerge as a potential treatment and valuable supplement for the patients inflicted by this devastating disease. Vitamin D is an important member of the fat soluble vitamins group. It acts as a hormone involved in the maintenance of calcium homeostasis and the regulation of cell proliferation and differentiation, where it has both endocrine and paracrine actions. Calcitriol (active form of vitamin D) acts as a steroid hormone, binding to a nuclear receptor protein in target tissues and regulating gene expression. It also plays a role in the immune system function. In the current situation, the vitamin D levels have been correlated to the disease severity of the COVID-19 patients. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 1 Vitamin D Synthesis and Metabolism: Overview Vitamin D can be obtained by us in majorly three ways, either as dietary sources in the form of vitamin D3 and D2. Vitamin D3 or cholecalciferol is majorly synthesized in the skin and D2 form or ergocalciferol can be obtained by plants, yeast or fungi when they are exposed to UV-B. Both of these forms of vitamin D are hydroxylated and finally converted to the single active form, the 1, 25-dihydroxycholecalciferol. The major sources of vitamin D include milk, egg yolks, oily fish/ liver, mushrooms etc. When ingested, vitamin D or cholecalciferol, being fat soluble, enters the blood stream via the intestine being absorbed in the form of micelles that are converted to chylomicrons, which are then taken to the liver. But the dietary sources of vitamin D are not as important, as the major synthesis occurs in the skin. The 7-dihydrocholesterol in the skin when exposed to sunlight or UV radiation, gets converted to cholecalciferol (calciol), which is then bound to the plasma Vitamin D binding proteins and taken to the liver. The third source of vitamin D can be in the form of supplements. The liver has the enzyme called 25-hydroxylase that can add a hydroxyl group to the cholecalciferol 25th carbon thus converting it to 25-hydroxycholecalciferol, both the dietary and the endogenously (in skin) synthesized vitamin D undergo this conversion in liver. Unlike other vitamins, the human liver does not store vitamin D in large amounts, the amount of stored vitamin D never exceeds 25 nmol per kg, but some amounts of vitamin D are sequestered in the adipose tissues, which are released when this fat is catabolized. The major amounts of vitamin D are present in plasma as calcidiol that has a half-life of three weeks. From the liver the 25-hydroxycholecalciferol then travels to the kidney where the enzyme 1-α-hydroxylase adds a hydroxyl group to the first carbon and converts it to 1, 25dihydroxycholecalciferol (calcitriol), which is the active form of vitamin D and acts in the intestines to regulate the calcium absorption and the calcium homeostasis in the body. In most tissues the major pathway for the inactivation of calcitriol is by 24-hydroxylation to calcitetrol, then onward oxidation by way of the 24-oxo-derivative, 23-hydroxylation, and oxidation to calcitroic acid. Vitamin D is excreted mostly in the bile, less than 5% is excreted as water-soluble metabolites in urine. Some 2% to 3% of the vitamin in bile is in the form of cholecalciferol, calcidiol, and calcitriol, but most is a variety of polar metabolites and their glucuronide conjugates. Given the main physiological function of vitamin D is the calcium homeostasis the absorption of vitamin D is regulated by the calcium levels in the body. The vitamin D metabolism is controlled by 24-hydroxylase and1-α-hydroxylase [13]. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 2 Vitamin D and the Immune System Since the 19th century decreased vitamin D levels have been associated to an increased risk of infections. Many studies have been carried out to understand the relationship between vitamin D and infections, especially lung infections by viruses. In the Meta analysis performed by Martineau AR, Jolliffe DA, Greenberg L et. al it was found that vitamin D supplementation had a positive impact on preventing the acute respiratory infectious diseases, at least in the individuals that received a daily or weekly dose without any additional bolus dose of vitamin D, while the bolus doses were not found to be protective [1]. The earliest indications regarding the role of vitamin D in improving the immune system function came from studies on tuberculosis patients, when treated with cod liver oil. Later on further studies have shown that calcitriol can help strengthen the innate immunity, by increasing the antimicrobial effects of macrophages and monocytes, calcitriol enhances the chemotactic and phagocytic abilities of these cells. After the recognition of pathogens by the toll like receptors, these activated macrophages were found to showcase expression of 1-α-hydroxylase and vitamin D receptors (VDR). The interaction of calcitriol, VDR and Retinoid X receptor (RXR) activate the transcription of antimicrobial peptides (AMPs) such as β defensin and cathelicidins. Cathelicidins are antimicrobial peptides that act against Gram negative and Gram positive bacteria, fungi, parasites and enveloped viruses. These can also induce degranulation in granulocytes and result in the release of proinflammatory substances, cause the activation of more macrophages, thus increasing phagocytosis and their chemotaxis towards the infected area and induce the production of IL-1β, TNFα and IL-6 by monocytes/ macrophages. Cathelicidins also enhance the differentiation of immune cells by increasing expression of receptors on the Antigen Presenting Cells (APCs) as well as the dendritic cell (DC) function and differentiation, therefore, cathelicidins influence both the innate and adaptive immune response [6]. β defensins have a characteristic β sheet fold due to six disulfide bonds present between cysteine residues, these disrupt the integrity of membranes, such as the bacterial membranes as well as puncture holes into the envelope of viruses therefore causing destruction of the viral structure [6]. Besides the effects of AMP on dendritic cells, calcitriol also acts on DCs by changing their morphology and function to change their state into more tolerogenic and immature. In this state the DCs express lesser MHC class II and co stimulatory molecules such as CD40, CD80, CD86 which reduces their antigen presenting capacity and decrease in IL-12 production with an increase in IL-10 production which is tolerogenic. Vitamin D also inhibits the IL-2 and Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 3 IL-17, the TLR on monocytes as well as decreases the levels of proinflammatory IL-6. All of these effects maintain an anti-inflammatory or more tolerogenic immune response keeping a check on the proinflammatory/ autoimmune immune response. This is also achieved by repression of the T helper cell (Th) proliferation, differentiation and modulation of the cytokine production. The production of proinflammatory substances by Th1 (such as IL-2, Interferon-γ, TNF-α), Th9 (IL-9), and Th22 (IL22) are decreased. But the production of more anti-inflammatory substances such as Th2 cytokines (like IL-3, IL-4, IL-5, and IL-10) are increased. Calcitriol also acts on the T regulatory (Tregs) cells to help reduce the proinflammatory response either indirectly, via APCs such, as dendritic cells, which are maintained in an immature state by vitamin D, thus offer lower presentation of antigens, or by direct action, that involves the conversion of 25(OH)D to calcitriol by Tregs themselves [2]. The cytokine production and secretion by the immune cells is mediated on a transcription level by Vitamin D Receptor (VDR). The VDR is composed of a highly conserved DNA binding domain and an α-helical ligand-binding domain. The ligand-bound VDR activates transcription by heterodimerization with RXRs, which is essential for high-affinity DNA binding to cognate vitamin D response elements (VDREs) located in the regulatory regions of its target genes. When Vitamin D interacts with the VDR it causes a negative regulation of the NFκB and STAT 1/5 mediated signaling that in turn results in the decreased transcription of THF-α, IL-6, and IL-12β. The activation of VDR also causes intracellular glutathione level to increase, resulting in the regulation of Reactive Oxygen Species (ROS) that can otherwise contribute to proinflammatory signaling via NFκB signaling. The VDR activation also control IL-2 and IL-10 regulation via conformational and epigenetic changes in the promoter regions of these genes. Vitamin D can also exert the anti-inflammatory effects via non-genomic pathways that are initiated by the Plasma membrane VDR. Vitamin D binding to the membrane VDR can activate certain secondary messengers such as G protein-coupled receptors and phospholipase C. In some cases the non-genomic pathways may interact with genomic pathways and influence transcription of various genes [5]. It was found that in the case of patients with low serum Vitamin D levels, the proinflammatory pathways will be favored, and that will finally result in a situation known as the cytokine storm that creates a major risk for a Multiple Organ Dysfunction (MOD) in the patients that have a severe case of COVID-19. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 4 Vitamin D Effect on ACE2 The Angiotensin-converting enzyme 2 (ACE2) serves as the entry point for severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2) and ACE2 is a part of the renin-angiotensin system (RAS). The attachment of virus to ACE2 causes a decline in its expression thus making the lungs prone to severe injury and distress. The Angiotensinogen produced by the liver is cleaved by renin, produced by kidneys, into Angiotensinogen I which is then further cleaved into its active form, Angiotensin II by Angiotensin converting enzyme (different from ACE2). Angiotensin II interacts with AT1R and leads to vasoconstriction, sodium ion and water retention by the kidneys, it exerts a proinflammatory effect on the endothelial cells, vascular smooth muscle cells, can also increase the amounts of adhesion molecules, chemokines and cytokines, also promoting fibrosis and proliferation. Ang II starts an inflammatory cascade with ROS and NFκB which increases the expression of proinflammatory chemokines. The excess ROS can promotes a prothrombotic state [9]. The ACE2 is a membrane bound enzyme that converts the Ang II to Ang (1-7). The Ang (1-7) has an opposite function to Ang II and when it interacts with AT2R and MasR it leads to Vasodilation, diuresis, and decreases inflammation by limiting the release of inflammatory molecules, inhibits the signaling pathways involved in tissues fibrosis and those required for an atherosclerotic state [10]. Vitamin D serves as a negative endocrine RAS modulator, it inhibits the expression and production of renin. It causes the induction of ACE2/Ang-(1-7)/MasR axis activity, while inhibiting the renin and the ACE/Ang II/AT1R axis, resulting in an increase in the expression and concentration of ACE2, MasR and Ang-(1-7) and therefore showing a protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), which can be very important effect in case of COVID-19 patients. It was found that the vitamin D deficiency is linked to an increased risk of COVID-19 infection and the severity of cytokine storm. A prolonged deficiency of vitamin D may result in an activated RAS, thereby leading to a chronic CVD and decreasing the lung function as well as inducing RAS activated lung fibrosis. Patients with such comorbidities were found to constitute the higher proportion of critically ill cases in the COVID‐19 pandemic [8]. The suppression of renin gene by vitamin D is independent of Ang II feedback regulation. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 5 Vitamin D Supplementation in COVID-19 The daily recommended dose of vitamin D for an adult ranges from 2000 IU/ Day to 4000 IU/ Day (IU= 0.025μg). There are very less cases of vitamin D toxicity reported, thus overall vitamin D can be taken as a supplement quite safely. Multiple epidemiological studies have established that low vitamin D levels are directly linked to an increased incident of viral infection as well as Acute Lung Injury (ALI) severity in patients. A serum 25(OH)D level < 20 ng/mL is considered deficient while < 30 ng/mL as insufficiency. It was concluded that patients receiving a daily or weekly supplementation were more protected against Acute Respiratory Tract Infections (ARTIs) and the best results were observed when the 25(OH)D levels were >10.02ng/mL, than those receiving a bolus dose. In the case of severe or critically ill patients of COVID-19 that required a ventilator or admission into the intensive care unit (ICU) a prevalence of vitamin D deficiency was observed. Some studies have indicated that taking supplementation during the ICU days has not been very beneficial to these patients, while those who were administered vitamin D before, experienced less days in the ICU. Vitamin D supplementation is prescribed keeping in mind what group an individual falls into, such as seniors, patients with renal disorders, dark skinned people residing in higher latitudes, obese people, what kind of vitamin D sources are available and affordable by these individuals and whether they are at a high risk of deficiency or toxicity etc. To reach the optimal 25(OH)D plasma level (30–50 ng/mL), international guidelines recommend daily supplementation of 400 IU–2000 IU for the general population (based on age, sex, body weight, skin color, time outdoors, and geographic latitude) throughout the year. Adults deficient in vitamin D can take weekly doses of 50 000 IU for up to 3 months or daily doses of 6000 IU followed by maintenance doses of 1500–2000 IU/d after achieving optimal blood concentration. The recommended doses increase for pregnant and breastfeeding women, obese adults (body mass index > 30 kg/m2), seniors, night workers, and dark-skinned people, as well as patients with a disability; and decrease for neonates and children. In the current scenario, a dose of 60,000 IU/Day in the form of tablet twice daily is being given to severely affected patients of COVID-19 which also have vitamin D deficiency [12]. Even though acute vitamin D toxicity is very rare, it is defined by blood 25(OH)D concentration > 150 ng/mL. As per the most recent evidence, the chronic toxicity appears after daily intake of > 40 000–60 000 IU for ≥ 1 months consecutively [12]. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 6 Conclusion The adequate levels of vitamin D have been associated to reduction in the risk of viral respiratory tract infections as it is involved in the regulation of ACE2 activity that serves as the major entry point for coronavirus. Vitamin D also enhances the physical barrier by regulating proteins of tight junctions and adhesion molecules. It strengthens the innate immune response by stimulating the production of antimicrobial peptides such as the β defensins and cathelicidins that are involved in destruction of the viral structure. Vitamin D also favors the succession of anti-inflammatory pathways in the immune system by modulating the adaptive immunity players such as Th2 (produces IL-4, IL-5, IL-10, IL-13) and decreasing the activity of inflammation promoting cells, the Th1 cells (produce proinflammatory cytokines such as IL-6, IFN-γ and TNF-β) which it achieves by inhibiting NFκB. This shift caused by vitamin D indirectly helps reduce the cytokine storm which is a major reason for death in severely ill patients. All of these finding have revealed a new way of treatment and even prevention of severe illness caused by the SARS-CoV-2. Doctors have now started prescribing vitamin D doses as a supplement to healthy as well as affected individuals to avoid or curb with the disease. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 7 References 1. Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Janssens W, Jensen ME, Kerley CP, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S, Stelmach I, Trilok Kumar G, Urashima M, Camargo CA, Griffiths CJ, Hooper RL. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess. 2019 Jan;23(2):1-44. doi: 10.3310/hta23020. PMID: 30675873; PMCID: PMC6369419. 2. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013 Jul 5;5(7):2502-21. doi: 10.3390/nu5072502. PMID: 23857223; PMCID: PMC3738984. 3. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32(7):1195-1198. doi:10.1007/s40520-020-01570-8 4. Radujkovic A, Hippchen T, Tiwari-Heckler S, Dreher S, Boxberger M, Merle U. Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients. 2020;12(9):2757. Published 2020 Sep 10. doi:10.3390/nu12092757 5. Calton EK, Keane KN, Newsholme P, Soares MJ. The Impact of Vitamin D Levels on Inflammatory Status: A Systematic Review of Immune Cell Studies. PLoS One. 2015;10(11):e0141770. Published 2015 Nov 3. doi:10.1371/journal.pone.0141770 6. Karim Y, Turner C, Dalton N, Roplekar R, Sankaralingam A, Ewang M, Fogelman I, Hampson G. The relationship between pro-resorptive inflammatory cytokines and the effect of high dose vitamin D supplementation on their circulating concentrations. Int Immunopharmacol. 2013 Nov;17(3):693-7. doi: 10.1016/j.intimp.2013.08.010. Epub 2013 Sep 3. PMID: 24007780. 7. van Harten RM, van Woudenbergh E, van Dijk A, Haagsman HP. Cathelicidins: Immunomodulatory Antimicrobials. Vaccines (Basel). 2018;6(3):63. Published 2018 Sep 14. doi:10.3390/vaccines6030063 8. Di Rosa M, Malaguarnera M, Nicoletti F, Malaguarnera L. Vitamin D3: a helpful immuno-modulator. Immunology. 2011;134(2):123-139. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 8 9. Malek Mahdavi A. A brief review of interplay between vitamin D and angiotensinconverting enzyme 2: Implications for a potential treatment for COVID-19. Rev Med Virol. 2020;30(5):e2119. doi:10.1002/rmv.2119 10. Dandona, P., Dhindsa, S., Ghanim, H. et al. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens 21, 20–27 (2007) 11. Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes-E-Silva AC. The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research. Curr Drug Targets. 2017;18(11):1301-1313. doi: 10.2174/1389450117666160727142401. PMID: 27469342. 12. Hadizadeh F. Supplementation with vitamin D in the COVID-19 pandemic?. Nutr Rev. 2021;79(2):200-208. doi:10.1093/nutrit/nuaa081. 13. David. A. Bender, Nutritional Biochemistry of the Vitamins, second edition, Cambridge. Academia Letters, November 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Nidhi Bhasin, nidhibhasin98@gmail.com Citation: Bhasin, N. (2021). Vitamin D Correlation to COVID-19. Academia Letters, Article 3835. https://doi.org/10.20935/AL3835. 9