Vitamin D3 as Potential Treatment Adjuncts for COVID-19

Abstract

Severe acute respiratory syndrome coronavirus type (SARS-CoV2, also known as COVID-19), which is the latest pandemic infectious disease, constitutes a serious risk to human health. SARS-CoV2 infection causes immune activation and systemic hyperinflammation which can lead to respiratory distress syndrome (ARDS). ARDS victims are characterized by a significant increase in IL-6 and IL-1. Macrophage activation, associated with the "cytokine storm", promotes the dysregulation of the innate immunity. So far, without vaccines or specific therapy, all efforts to design drugs or clinical trials are worthwhile. Vitamin D and its receptor vitamin D receptor (VDR) exert a critical role in infections due to their remarkable impact on both innate and adaptive immune responses and on the suppression of the inflammatory process. The protective properties of vitamin D supplementation have been supported by numerous observational studies and by meta-analysis of clinical trials for prevention of viral acute respiratory infection. In this review, we compare the mechanisms of the host immune response to SARS-CoV2 infection and the immunomodulatory actions that vitamin D exerts in order to consider the preventive effect of vitamin D supplementation on SARS-CoV2 viral infection.

Keywords: SARS-CoV2 immunopathology; immunomodulation; prevention; vitamin D.

Figure 1

Vitamin D synthesis and mechanism of action. Vitamin D is biologically inactive and requires two enzymatic steps to become biologically active. Cutaneous 7-dihydrocholesterol is converted into preVitD₃ after irradiation by ultraviolet light (UVB) from the sun. The first step occurs principally in the liver, where cholecalciferol is hydroxylated to 25-hydroxy-VitD (25(OH)D) or calcidiol, by the cytochrome P450 hydroxylase enzymes CYP27A1 and CYP2R1. Then, 25(OH)D is further converted, through a second hydroxylation in the kidneys by the mitochondrial cytochrome P450 enzyme (CYP27B1), into the active 1,25-dihydroxyvitamin D3 (1α,25(OH)₂D₃) or calcitriol. The activity of 1α,25(OH)₂D₃ is regulated by 24-hydroxylation (carried out by CYP24A1), which inactivates the hormone. Vitamin D activation takes place not only in the kidneys but also in other organs. Vitamin D is also activated locally by CYP27B1 in many cells including those of the immune system, where it influences a multitude of cellular functions. Active 1α,25(OH)₂D₃ binds the vitamin D receptor (VDR) and, afterwards, interacts with vitamin D response elements (VDREs) to modulate gene transcription. PTH, Parathyroid Hormone; RXR, Retinoid X Receptor; Vitamin D, VIT D; VDBP, Vitamin D Binding Protein

Figure 2

Vitamin D deficiency, daily intake, and risk factors. The international guidelines that focus on pleiotropic effects of vitamins recommend a target 25(OH)D concentration of 30 ng/mL. Vitamin D doses, with a range between 400-2000 IU/day, are recommended based on age, limited sunlight exposure, ethnicity, skin pigmentation, gastrointestinal absorption disorders, obesity, diabetes mellitus, liver and kidney disease, alcohol intake. Acute toxicity can occur using an excess dose of 10,000 IU/day of vitamin D, which results in serum 25(OH)D concentrations >150 ng/mL (>375 nmol/L). That level is more than the IOM-recommended UL of 4000 IU/day. Potential chronic toxicity would result from administering doses above 4000 IU/day for extended periods, i.e., for years, that cause serum 25(OH)D concentrations in the 50–150 ng/mL (125–375 nmol/L) range [13].

Figure 3

Host–SARS-CoV2 interaction and Vitamin D action. SARS-CoV2 interacts with the host ACE2 receptor using a spike protein S1 that facilitates the binding of the virion to the cell. Infection generates “cytokines storm”. ACE2-expressing alveolar epithelial type II cells (AECII) help corona viral replication. 1α,25(OH)₂D₃ induces ACE2/Ang-(1-7) axis and inhibits renin and the ACE/Ang II/AT₁R cascade, and therefore prevents vasoconstriction, inflammation, cell proliferation, fibrosis, oxidative stress, and activates autophagy. ACE, Angiotensin Converting Enzyme; Ang II, Angiotensin II; AT₁R, Angiotensin type 1 receptor; AT₂R, Angiotensin type 2 receptor

Figure 4

Host immune response COVID19 infection and Vitamin D function. Toll-like receptors (TLRs) are able to recognize viruses and carry them to the endosome. Different TLRs induce various biological responses via activation of MyD88, TIRAP, TRIP, and TRAM. MyD88 activates the nuclear factor kappa B (NF-κB) pathways to induce inflammatory cytokines production. Unc-93 homolog B1(UNC93B1) is essential for signaling of TLR3, TLR7, and TLR9. It interacts TLRs in the endoplasmic reticulum (ER) following viral infection. After a TLR is activated by the matching PAMP, MyD88 recruits IL-1 receptor-associated kinase (IRAK)-4, and then induces IRAK4 to activate other members of the IRAK, such as IRAK1 and IRAK2. Then, IRAK4 activates NF-κB and MAPKs downstream of MyD88. IRAKs interacts with TNF receptor-associated factor (TRAF) 6 and activates NF-kB. TRIF is an adapter protein of TLR3 and TLR4. TRIF-dependent pathways activate NF-kB and IFN receptors (IRFs). They induce the expression of various interferon-stimulated genes (ISGs), which reduce infection by their antiviral and immunomodulatory actions. SARS-CoV recognizes TLR7 and induces the proinflammatory cytokines such as TNF-α, IL-6, and IL-12. Coronaviruses inhibit type I IFN production and prevent the signaling downstream by inhibiting IRF3 nuclear translocation. 1α,25(OH)₂D₃ promotes TLR2 and TLR4. In response to TLR2/1 activation in human macrophages, 1α,25(OH)₂D₃ promotes innate immunity effectors and induces the synthesis of cathelicidin. MyD88, Myeloid differentiation primary response 88; TRAM, TRIF-related adaptor molecule; TIRAP, TIR domain-containing adapter protein; TRIP, TRAF-interacting protein.

Figure 5

Positive and negative effects of vitamin D in immunomodulation against SARS-CoV2. DCs, Dendritic Cells; iNOS, inducible Nitric Oxide; NETs, neutrophil extracellular traps.