key: cord-0977577-8eeoswsp authors: Saxena, Priyanka; Nigam, Kumud; Mukherjee, Sayali; Chadha, Sonia; Sanyal, Somali title: Relation of Vitamin D to COVID-19 date: 2021-12-14 journal: J Virol Methods DOI: 10.1016/j.jviromet.2021.114418 sha: 33b0a8e9a8afb77df03a74abacf634b114ba0970 doc_id: 977577 cord_uid: 8eeoswsp The coronavirus pandemic has lasted for more than a year now and still remains the leading cause of concern, worldwide. The causal agent; SARS- CoV-2, leads to the development of respiratory distress in the lower respiratory tract, sometimes leading to fatalities. Keeping in mind the discovery of mutant strains across the world, as well as the delay in vaccinations across vast populations, most people speculate boosting their immune systems as a preventive and precautionary measure. One of the most commonly observed conditions that hamper immunity; Vitamin D deficiency has been linked to the onset and the alteration of course of the disease in patients and is also being explored as a potential drug supplement. These surmises make it essential to study deep into the speculations. This review aims to overview the possible correlations between Vitamin D and COVID-19. Vitamin D or calciferol is an immunomodulatory substance that is obtained generally from exposure to sunlight and some foods. When obtained from sun exposure, it is inactive and must Covid-19 is caused by SARS-CoV-2, an RNA virus transmitted through respiratory droplets. The spike protein present on the surface of SARS-CoV-2 binds to the ACE2 (angiotensin converting enzyme) receptor on the host cells of the nose and respiratory tract. Immune response against the virus includes uncontrolled non-specific inflammation and cytokine release which cause injury to lung and other vital organs. Vitamin D has been noted to inhibit the pro-inflammatory cytokine secretion and manipulate the ACE2 receptors through which the virus manifestation spreads apart from being an immunomodulator that affects both innate and adaptive immune responses. A study conducted by Radujkovic on 185 hospitalized and home quarantined subjects showed a clear inverse relationship between the magnitude of the disease and the levels of vitamin D on admission. Out of these, 50% who were hospitalized showed characteristic Vitamin D deficiency (i.e, vitamin D levels less than 12 ng/mL) as compared to the 50% outpatients. This inpatient cohort also sustained more cases of oxygen therapy along with invasive mechanical ventilation and death. The study concluded that there was noted a 6 fold higher hazard of developing severe J o u r n a l P r e -p r o o f disease and a whopping 15 fold higher risk of death due to disease (2) . Another study by Meltzer et al concluded that the risk of contracting the virus was 1.77 times higher in patients with vitamin D Deficiency (3). Kaufman and colleagues elucidate an inverse relationship between the level of vitamin D and SARS-CoV-2 positivity rate. People with less than 20 ng/mL of Vitamin D showed 54% higher SARS-CoV-2 positivity rates when compared with the test population having Vitamin D levels higher than 55 ng/mL (4) . The study concludes that an increase in the serum levels of 25(OH)D in patients decreased the risk of developing severe ramifications of the coronavirus. Immunopathogenesis of SARS-CoV-2 begins with its attack on the epithelial cells of the respiratory tract followed by its carriage to the nasal, bronchus, and mucosa-associated lymphoid tissue (NALT, BALT, MALT) for colonization and infiltration. The most highlighted complications of COVID-19 arise due to an increased amount of cytokines in the body. This exceptional release of pro-inflammatory cytokines is known as a cytokine storm. According to Fiorino et al., the release of cytokines can be studied as a property of the virus' N Protein (5) . Direct binding of spike viral protein to the NF-kB subdomains can induce synthesis of interleukins 17, 6, 8,1, and TNF alpha. Binding of virus to TLR of immune cells releases pro-IL-1β. Fever, fibrosis, and inflammation result from the cleavage-based activation of this interleukin. Whereas, binding of viral N protein AP-1 (Activator protein 1) can activate the IL-1 gene transcription which leads to the release of the pro-inflammatory IL-1 alpha. By activation of the COX-2 genes, SARS-CoV-2 can induce IL-8 which can create a local inflammatory environment and elevate the inflammatory response. This entire process has been pictorially described in Fig.1 An exceptional correlation can be traced between the higher mortality due to COVID-19 in males above 50 years of age and difference in sex hormones between the two genders. suffering from hypertension or heart conditions are due to the higher activity of serum ACE2. (7) Another conclusion notes the anti inflammatory role of estrogens found in higher quantities in women by virtue of sex. They also hint at a potential shielding role of estrogen as it decreases the COVID-19 infection by modulating the pro-inflammatory signaling pathways. (8) Bennink et al. note that the most pronounced difference between female and male patients (especially over the age of 50 years) is the manifold increased testosterone in men as compared to women. The reason for considering testosterone suppression as therapy for COVID-19 is due to its role in entry of virus via host cellular protein TMPRSS2 which is an androgen-regulated protease that primes the viral spike protein. Another alternative is to explore the potential of estrogen therapy as it is linked to stimulation of antibody production along with the reduction of innate immunity and cytokine storms. (9) SARS-CoV-2 is an infective agent that attacks the human body by manipulating the cytokine components of its immune system. Overwhelming levels of pro-inflammatory cytokines such as the IL-1, IL-6, and TNF alpha have been noted to cause severe complications of COVID-19 in form of ARDS (acute respiratory distress syndrome.) Mohan and colleagues explicate that the activity of vitamin D is much like a double-edged sword as it lowers acquired immunity while elevating innate immunity as their dominant function (10) . Subsidiary to this dominant enhancement of the innate immune system, it has also been opined that Vitamin D plays an efficient role in the regulation of adaptive immunity (11, 12) . This is achieved mainly due to the involvement of 1,25D in the regulation of T cell phenotypes, principally the naive Th cells. They also act on cytotoxic cells like the CD8+ cells and also promote the suppressor T regulatory cells (13) . Murdaca concluded that the upregulation or increased production of anti-inflammatory cytokines and Th2 cytokine ultimately leads to Th1 inhibition. They also propose the downregulation of Th1 cytokines like TNF-alpha and IFN-gamma which are pro-inflammatory in nature (14) . On one hand, it reduces the levels of pro-inflammatory cytokines by shifting proliferating T cells from Th1 to Th2 which protects the system from causing immune-mediated injury. Vitamin D has been studied to downregulate the TH1 cytokines such as the IFNγ along with repressing the effector T cell differentiation which results in decreased release of IL-12. Daniel and colleagues note that this micronutrient also restrains differentiation of naive TH-o Angiotensin-converting enzyme (ACE) 2 is a homolog to the carboxypeptidase ACE, which generates angiotensin II, the main active peptide of renin-angiotensin system (RAS). It has been determined that ACE2 receptors have a key role in the pathogenesis of SARS-CoV-2. J o u r n a l P r e -p r o o f C reactive protein is a pentameric protein indicative of inflammation in the body when found in higher than normal levels in the blood. CRP is a hepatic origin protein, the levels of which have been seen to remain inflated in cases of H1N1 influenza, avian flu H7N9 (22) , as well as COVID-19 (23) . Low-grade inflammation and thus increase in CRP levels are usually observed in people who suffer from vitamin D deficiency. A clearer outline of this inter-connected mechanism running between CRPs and Vitamin D has been outlined in Fig.3 . Daneshkhah and colleagues have postulated that due to increased low-grade inflammation in vitamin D deficient patients of ages 60 and above show 34% more incidences of high CRP (24) . It is hence predicted that enhancement in levels of vitamin D can reduce risks associated with cytokine storm and CRP in severe COVID-19 patients. showed significant effects of high dose calcifediol treatment in the patients hospitalized due to Covid-19. Of the 76 patients included, 50 were treated with calcifediol and 36 were given regular treatment without calcifediol. It was noted that in the calcifediol group, 2% of patients required ICU admission, and no deaths were recorded while in the regular group, 36% of patients required ICU admission, and 5.5% of patients recorded death (33) . As per the flexible approach in the current COVID-19 pandemic, authors recommend mass administration of vitamin D supplements to populations at risk for COVID-19. It is clear to see that Vitamin D does more than just making our bones stronger and preventing osteoporosis. It is in fact one of the compounds which have extensive effects on the human body whether it be in regards with manipulating the immune responses or with regards to the regulation of disease pathogenesis. The ability of Vitamin D to counteract the pro-inflammatory activity of SARS CoV makes it an impressive substitute therapy for dealing with patients of the disease. Due to lack of extensive study and research in the field of the effect of Vitamin D in corona virus patients it is yet unclear to say how extensively Vitamin D controls the disease pathogenesis. 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