The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has led to a declaration of a Public Health Emergency of International Concern by the World Health Organization. As of May 18, 2020, there have been more than 4.7 million cases and over 316,000 deaths worldwide. COVID-19 is caused by a highly infectious novel coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to an acute infectious disease with mild-to-severe clinical symptoms such as flu-like symptoms, fever, headache, dry cough, muscle pain, loss of smell and taste, increased shortness of breath, bilateral viral pneumonia, conjunctivitis, acute respiratory distress syndromes, respiratory failure, cytokine release syndrome (CRS), sepsis, etc. While physicians and scientists have yet to discover a treatment, it is imperative that we urgently address 2 questions: how to prevent infection in immunologically naive individuals and how to treat severe symptoms such as CRS, acute respiratory failure, and the loss of somatosensation. Previous studies from the 1918 influenza pandemic have suggested vitamin D's non-classical role in reducing lethal pneumonia and case fatality rates. Recent clinical trials also reported that vitamin D supplementation can reduce incidence of acute respiratory infection and the severity of respiratory tract diseases in adults and children. According to our literature search, there are no similar findings of clinical trials that have been published as of July 1st, 2020, in relation to the supplementation of vitamin D in the potential prevention and treatment for COVID-19. In this review, we summarize the potential role of vitamin D extra-renal metabolism in the prevention and treatment of the SARS-CoV-2 infection, helping to bring us slightly closer to fulfilling that goal. We will focus on 3 major topics here: 1. Vitamin D might aid in preventing SARS-CoV-2 infection: Vitamin D: Overview of Renal and Extra-renal metabolism and regulation. Vitamin D: Overview of molecular mechanism and multifaceted functions beyond skeletal homeostasis. Vitamin D: Overview of local immunomodulation in human infectious diseases. Anti-viral infection. Anti-malaria and anti-systemic lupus erythematosus (SLE). 2. Vitamin D might act as a strong immunosuppressant inhibiting cytokine release syndrome in COVID-19: Vitamin D: Suppression of key pro-inflammatory pathways including nuclear factor kappa B (NF-kB), interleukin-6 (IL-6), and tumor necrosis factor (TNF). 3. Vitamin D might prevent loss of neural sensation in COVID-19 by stimulating expression of neurotrophins like Nerve Growth Factor (NGF): Vitamin D: Induction of key neurotrophic factors. .

Keywords: 1,25(OH)2D3; 25(OH)D; COVID-19; Coronavirus; Extra-renal; IL-6; Immunomodulation; Infection; Metabolism; NF-kB; NGF; TNF; Vitamin D.

Fig. 1

Schematic overview of vitamin D metabolism and functions. Conversion of pro-hormone 25(OH)D to 1,25(OH)₂D₃ occurs primarily in kidneys, which is catalyzed by the enzyme CYP27B1 and released systemically to maintain skeletal homeostasis including calcium and phosphate metabolism. PTH is the main hormone in calcium homeostasis, regulating systemic calcium levels through its regulation of renal CYP27B1. Expression of CYP27B1 in extra-renal tissues has been demonstrated, which supports local synthesis of 1,25(OH)₂D₃ to act as immunosuppressant during the inflammation or invasion of microbe. The regulatory loop of extra-renal CYP27B1 and local synthesis of 1,25(OH)₂D₃ is not fully understood

Fig. 2

Overview of vitamin D’s immunomodulation functions. Innate immune response: Vitamin D inhibits the maturation of dendritic cells and blocks their antigen presentation to T helper cells. Also, vitamin D induces the differentiation of macrophages and exerts direct antibacterial and antiviral actions through induction of cathelicidin and defensin peptides. Adaptive immune response: Vitamin D modulates the balance of T-helper subsets by inhibiting Th1 and Th17 effector cells, inducing Th2 cells, and enhancing the development of Treg cells. Vitamin D suppresses the release of pro-inflammatory cytokines including IL2, IL6, IL12, INFr, TNFa, NF-kB, etc., from both innate and adaptive immune responses

Fig. 3

Mechanism of vitamin D’s Anti-Viral Functions. (1) Induction of virus-specific CD8 + T cells (EBV and Influenza). (2) Induction of cathelicidin and HBDs (EBV, Influenza, and HIV). (3) Blocking of viral entry and replication (Influenza, HIV, HCV). (4) Induction of autophagy and apoptosis (EBV, Influenza, HIV, Rota). (5) Suppression of Toll-like Receptors like TLR2, TLR7, and TLR9 (Dengue)

Fig. 4

Schematic overview of vitamin D treatment of human diseases. Vitamin D deficiency is common. Low levels of vitamin D have been reported to be involved in the pathogenesis of various human diseases including autoimmune diseases like SLE, cytokine release syndrome, somatosensory defects, osteoporosis, and infections like influenza and dengue. Vitamin D supplementation is required for maintaining a balanced immune system to fight pathogens and prevent autoimmune diseases. The green box indicates the mechanism of the diseases. The blue box indicates immunomodulatory effects of vitamin D