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

COVID-19 is an infectious disease caused by SARS-CoV-2, a newly discovered coronavirus that primarily spreads between people during close contact and through respiratory droplets when infected individuals cough, sneeze, or talk [1‐3]. Furthermore, infection might occur from the touching of a contaminated surface and subsequent contact with the face [3]. SARS-CoV-2 is an enveloped and single positive-stranded RNA virus (~ 30 kb in length) with a nucleocapsid, which undergoes endocytosis or membrane fusion to enter the infected cells and can cause respiratory, enteric, hepatic, and neurological diseases in different species including humans [4]. Mechanistically, SARS-CoV-2 has spike (S) glycoproteins comprised of two functional subunits called the S1 protein which binds to the host cell receptor and the S2 protein which promotes fusion of the viral and cellular membranes [5]. Angiotensin Converting Enzyme II Receptor (ACE2) has been identified as a functional receptor for SARS-CoV-2 entry into the cell [6‐8], and ACE2 expression is high in the lung, heart, ileum, kidney and bladder [9]. At this time, there are no specific vaccines or treatments for COVID-19, and older adults with underlying comorbidities are at higher risk for severe illness [10]. Thus, important information for most people is to know how to enhance their immune system to prevent SARS-CoV-2 infection or control the severity of disease progression to avoid the next waves of the deadly COVID-19 pandemic [11].

The last century’s influenza pandemic (1918–1919) claimed between 40 and 50 million lives [12]. A substantial proportion of deaths were found to occur greater than 2 weeks after symptom onset, suspected to be caused by cytokine storms [13]. Unfortunately, the second and third waves of the 1918–1919 pandemic were much more deadly than the first one because the H1N1 virus had mutated to a deadlier form and spread worldwide faster [14]. Analyzing data during the 1918–1919 pandemic revealed an inverse association between solar ultraviolet B (UVB) irradiance and case fatality rate, suggesting that vitamin D might have played a role in reducing the development of pneumonia and improving case fatality rates [15]. The lowest pneumonia and case-fatality rates were found in the region with the highest solar UVB irradiance and lowest latitude in San Antonio, Texas, while the highest rates were in New London, Connecticut, which had the lowest UVB irradiance and highest latitude. It seems that a similar phenomenon is occurring in the first wave of the current COVID-19 pandemic [16].

Vitamin D is a group of fat-soluble steroids, and the most common forms of vitamin D supplementation are cholecalciferol (Vitamin D₃) and ergocalciferol (Vitamin D₂), precursors of 1,25(OH)₂D₃ (the active form of vitamin D) [17]. New developments in measurement of vitamin D metabolites for both clinical diagnosis and research practice has greatly advanced our understanding of Vitamin D’s role in human health in the last decade [18]. Vitamin D is involved in essential biological roles (classical) including bone metabolism, calcium and phosphorus homeostasis, and recently discovered roles (non-classical) involving immunomodulation, lung and muscle function, cardiovascular health, and infectious disease prevention [17, 19, 20]. In COVID-19 patients, type-II alveolar epithelial cells (pneumocytes) are the primary target of SARS-CoV-2, and their impairment decreases the surfactant level and increases the risk of acute respiratory distress syndrome (ARDS) [21, 22]. Vitamin D has been reported to reduce apoptosis of pneumocytes and stimulate surfactant synthesis in these cells to prevent severe lung injuries such as ARDS [23, 24]. Vitamin D sufficiency is widely defined as a serum 25-hydroxyvitamin D (25(OH)D) level greater than or equal to 30 ng/ml (75 nmol/L), while insufficiency is defined as 20 to 30 ng/ml (50–75 nmol/L), and deficiency is a level lower than 20 ng/ml (50 nmol/L) [25]. A low level of vitamin D is common in the elderly and has been associated with all-cause mortality including sepsis, and that supplementation of vitamin D could significantly reduce overall mortality [26, 27]. Besides geographic and climate factors, vitamin D deficiency is also more prevalent among individuals with darker skin than those with a lighter skin color due to the fact that heavy pigmentation reduces vitamin D production in the skin [28]. Furthermore, an additional burden of obesity or chronic diseases make them much more susceptible to H1N1 or COVID-19. Previous clinical trials reported that vitamin D supplementation can reduce incidence of acute respiratory infection and the severity of respiratory tract diseases in adults and children [29, 30]. The purpose of this review is to provide an overview of vitamin D’s newly discovered non-classical functional roles in immunomodulation to prevent viral infection, inhibit CRS, and reveal the importance of understanding vitamin D extra-renal metabolism in pursuit of alternative benefits of vitamin D supplementation. In addition, we hypothesize that maintaining a healthy baseline level of vitamin D may lead to improved outcomes in COVID-19 patients, including many minorities.

It is increasingly recognized that localized synthesis of 1,25(OH)₂D₃ rather than systemic production is responsible for many of the immune effects of vitamin D in respiratory diseases [73]. Extra-renal expression of CYP27B1 has been found in alveolar macrophages, dendritic cells, lymphocytes, and epithelia, which form 1,25(OH)₂D₃ locally to act in an autocrine or paracrine fashion to modulate cell proliferation, cell differentiation and inflammation [62, 73]. At the beginning stages of acute inflammation (elicitation phase), vitamin D inhibits proliferation of Th1 and Th17 cells and the abnormal release of their cytokines (IFN-γ, TNF-α, IL-1, IL-2, IL12, IL-23 and IL-17, IL-21) [74]. During the resolution phase of inflammation, vitamin D-mediated differentiation of Th2 cells and release of their cytokines (IL-4 and IL-10) are important to avoid organ damage through an excessive immune response. Mechanistically, vitamin D treatment can decrease mRNA expression of IFN-β and interferon-stimulated genes in respiratory syncytial virus (RSV) [63]. Downregulation of pro-inflammatory cytokines is another important mechanism by which vitamin D exerts its immunomodulatory effects in the pulmonary infection. It has been reported to reduce downstream targets of TNF-α, directly modulate NF-κB activity in immune cells and indirectly inhibit NF-κB signaling by upregulating the expression of insulin-like growth factor binding protein-3 (IGFBP-3) [75]. Additionally, vitamin D can decrease expression of IL-6 through MAPKs/P38 signaling pathway [76]. IL-6 was thought to play a key role in the cytokine storm associated with serious adverse outcomes and lower NK cell numbers in patients infected with SARS-CoV-2 pneumonia [48]. Anti-IL6 treatment is in clinical trial for severe respiratory failure in COVID-19 (ClinicalTrials.gov Identifier: NCT04322773). In addition, there are ongoing clinical trials of vitamin D in prevention and treatment of autoimmune diseases by utilizing its immunomodulatory function (Studies 10–12, Table 1). Considering its role as a strong immune-suppressor, vitamin D supplementation might help inhibit abnormal immune response and cytokine storm in COVID-19.

Some COVID-19 patients have neurological symptoms—loss of taste and smell, headaches, etc. How SARS-CoV-2 affects the nervous system has not been well studied because few autopsies of these patients have been done due to the highly contagious virus. Previous evidence from studies of SARS-CoV have demonstrated the presence of SARS-CoV in neurons of the brain from SARS patients [77], and suggest that the coronavirus might target the nervous system through the olfactory bulb [78]. It’s possible that SARS-CoV-2 can infect nerve cells, particularly neurons in the nervous system and cause nerve damage leading to neurological symptoms in COVID-19 [79].

Previous studies have revealed that vitamin D has a potent neuroprotective effect through several independent mechanisms [80]. The neuroprotective action of vitamin D is associated with regulation of neurotrophins, which are important for survival, differentiation, and maintenance of nerve cells in both peripheral and central nervous systems [81]. Vitamin D stimulates expression of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), glial neurotrophic factor, and also neurotrophin receptor p75^NTR in neurons, glial cells, and schwann cells. Neurotrophin induction underlies the neuroprotective effect of vitamin D in brain ischemia and neurodegenerative disorders. For example, vitamin D can decrease the progression of Alzheimer’s disease through the induction of NGF [81].

The immunomodulating properties of vitamin D represent another mechanism of its activity as an immunosuppressant to protect neurons [82]. Vitamin D has been reported to promote the migration and differentiation of oligodendrocyte progenitors and enhance remyelination of neurons to improve neurotransmission in diseased rats [83]. There are ongoing clinical trials of vitamin D in prevention and treatment of neurological diseases by utilizing neuroprotective effects (Studies 13–15, Table 1). Our hypothesis is that vitamin D might improve anosmia-like symptoms and prevent neurological complications in COVID-19.

There is a plethora of evidence that vitamin D is required for normal immune function for fighting pathogens and preventing autoimmune diseases [75, 97‐101] (Fig. 4). Published clinical trial data also demonstrated the potential of vitamin D supplementation to prevent acute respiratory infection through modulating the innate immune response [29, 66] and boosting antibody production after vaccination [30, 102]. While there are various outcomes regarding the benefit of vitamin D supplementation in the clinical research, the clear association between low levels of 25(OH)D or 1,25(OH)₂D₃ and pathogenesis of a wide variety of infectious and autoimmune diseases is warranted for further investigation of vitamin D supplementation (readily available and affordable) as a potential agent to prevent viral infection and improve the survival outcome. Hence, we hypothesize that vitamin D supplementation will help COVID-19 patients maintain sufficient serum levels of vitamin D as guideline recommended [91, 103], allowing inflammation-upregulated CYP27B1 in respiratory epithelia and immune cells to generate a local high dose of 1,25(OH)₂D₃ to inhibit CRS and disease progression. Serum calcium level should be monitored and if significantly elevated, it can be mitigated by hydration or a dose adjustment of the vitamin D supplement. There is no current Food and Drug Administration (FDA)-approved vitamin D treatment for diseases. However, section 101.72 of FDA (revised as of April 1, 2019) mentioned that adequate calcium and vitamin D may reduce the risk of osteoporosis. In the era of overwhelming COVID-19 disease burden, the risk and benefit of such trials (Additional file 1: Table S1: 21 ongoing vitamin D clinical trials for COVID-19 with detailed information, as of July 2nd, 2020) is highly favorable while no specific therapy or vaccine is available for COVID-19 currently.