Apart from its functions in calcium homeostasis and the maintenance of the skeletal system, vitamin D has played a critical role in the human immune system. Receptors for its active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D), have been found in cells of the immune system, including B cells, T cells, and such antigen-presenting cells (APCs) as macrophages and dendritic cells, which have the 1α-hydroxylase enzyme (CYP27B1) that synthesizes Vitamin D from its precursor, 25-hydroxyvitamin D (25-OHD)3, 1. Strikingly, such a synthesis is entirely independent of regulation by the Parathyroid Hormone (PTH), inducible by cytokines, and ultimately regulated by the abundance of 25-OHD, which makes the CYP27B1 of immune cells exclusively dissimilar to its renal counterpart. The availability of the receptors (Vitamin D Receptors; VDR) and CYP27B1 in cells of the immune system allows them to generate active Vitamin D autonomously and to utilize it instantaneously. Such a provision suggests an autocrine activity of Vitamin D in the immunological sphere and its overall role in the body’s defense mechanisms. Moreover, CYP27B1 has also been found in epithelial cells, which constitutes the first line of defense and plays a crucial role in mediating local immune responses, including instigating inflammation and recruiting immune cells via cytokine and chemokine molecules19. Accordingly, a conceptualization about the immunological functions of the steroidal hormones has taken root, which has helped to explicate the correlation between low serum 25-OHD levels and proneness to infections, as demonstrated by multiple studies in the past20, 21, 22, 23, 24, 25.

As mentioned previously, the coexistence of CYP27B1 and VDRs in cells of the immune system is part of an autocrine mechanism for defense against pathogens. One way such a mechanism acts is by promoting the secretion of antimicrobial peptides like β-defensin 2 (BD2) and cathelicidins26. For instance, the complex between 1,25(OH)₂D and VDR can bind with the promoter of the cathelicidin gene, expediting the transcription process and expanding the number of cathelicidins available for antimicrobial activities27, 28. This capability of the vitamin was proven in a previous study which found a superior level of cathelicidin expression in individuals with high serum 25-OHD levels29 and found to be emulated in lung epithelial cells30.

When released, cathelicidins can either directly extinguish pathogens of sundry sorts or neutralize the toxins, thus performing an immeasurably vital task in innate immunity31. In viral infections, the antimicrobial peptide is efficacious at combating viruses and curtailing their replications32, 33, 34, 35. This particular ability is also seen with BD-2, which could also stimulate the secretion and action of cytokines and chemokines responsible for the recruitment of immune cells to the site of infection36, 37, 38, 39. Together, BD-2 and cathelicidins are potent tools of the body to thwart pathogens and preclude the dilapidation of illness.

Interestingly, the expression of both the CYP27B1 enzyme and VDRs, or more obliquely the amount of 1,25(OH)₂D endogenously synthesized by immune cells, is influenced by the availability of pathogens, or more accurately, the abundance of Pattern Recognition Receptors (PRRs) that bind with them40, 41. Such an arrangement enables the immune cells to ratchet up their secretion of antimicrobial peptides upon detection of the pathogens they are meant to eliminate. However, it is not the only Vitamin D-related innate defense mechanism the human body employs when menaced by viruses.

One of the most rudimentary apparatuses in the body’s defense against any pathogen is barriers, which are principally upheld by cellular junctions—especially those of the epithelia—where Vitamin D wields excellent relevance. The 1,25(OH)₂D/VDR complex is capable of activating multiple signaling pathways responsible for the regulation of junction proteins and conferring structural integrity and functionality (such as in transport) to tissues42. To elaborate, VDRs have been shown to bind with the promoter sequence for the genes of proteins in the Claudin family which are essential to tight junctions and regulate their production43, 44, 45. There have also been indications that they are involved in regulating Occludin and ZO-1 proteins, which are integral to the junctions46, 47. For SARS-CoV-2, a virus that targets the respiratory system, it could be positively impacted by the modus operandi of Vitamin D, which has been shown to minimize lung permeability, strengthen pulmonary epithelial barriers against pathogenic invaders, and reduce the vulnerability to respiratory diseases48, 49.

Additionally, Vitamin D can also induce the procedures of autophagy, which is undertaken in cells infected with the pathogen and in cancerous cells50. This could be done through the upregulation of Beclin1, which can account for autophagy upon binding with class III phosphatidylinositol 3-kinase, or the downregulation of mammalian target of rapamycin (mTOR), which acts at various steps of the autophagy pathway to inhibit the process of cellular self-devouring51. As autophagy proceeds in a virus-borne cell, viral particles are bound for lysosomal degradation and antigen presentation, which would kickstart the type I Interferon (INF) antiviral pathway, thereby repressing viral replication and pathogenesis52, 53. The entirety of these factors above contributes to achieving the purpose of subjugating viral invaders in the human body.

While the SARS-CoV-2 virus itself can adversely affect the afflicted body in various ways, perhaps more concerning and threatening are the body’s own mechanisms in tackling it. Importantly, an extravagance in inflammatory responses embodied by the “cytokine storm” has been associated with the severity of COVID-19 and its associated mortality54, 55, 56, 57. It has also been reported as a chief cause of fatality for the Middle East Respiratory Syndrome (MERS), the early 2000s Severe Acute Respiratory Syndrome (SARS), and influenza, in general58.

Conventionally, a cytokine storm, or even a proportionate release of cytokines, starts with antigen presentation, which leads to the activation of cells in both the immunological domain and the surrounding tissues. This triggers the secretion of such pro-inflammatory signal molecules as Interleukin 1 (IL-1), Interleukin 6 (IL-6), Interleukin 8 (IL-8), Interleukin 10 (IL-10), Interferon Gamma (IFNγ), and Tumor Necrosis Factor Alpha (TNF-α)59. The secretions of these molecules proceed in a positive feedback loop60, and the higher their serum levels are, the more lung inflammation and damage they are accountable for61, 62. This can be explicated as the cytokines attract and activate immune cells like macrophages and neutrophils, which are then prompted to release leukotrienes and reactive oxygen species (ROS) in an attempt to destroy pathogens that unfortunately entail collateral damage upon surrounding tissues63. In the case of SARS-CoV-2 in the respiratory tract, such tissues are those of the alveoli and the encompassing capillaries, the destruction of which could result in acute lung injury (ALI) or, worse, the deadly acute respiratory distress syndrome (ARDS)64, 65. Moreover, activated neutrophils can also deploy their intracellular genetic material to set up neutrophil extracellular traps (NETs) designed to ensnare pathogenic intruders in an exorbitant amount in the occurrence of a cytokine storm, leading to the occlusion of blood vessels called “immunothrombosis”66.

The entirety of this constitutes the pathogenesis of COVID-19 and presents a distinct case as to the disease’s lethal quality. Intriguingly, it is also subject to the influence of Vitamin D, whose manifold functions include being an immunomodulator, among other functions7.

Understanding the immunomodulatory role of steroidal vitamin, one can experience insight into adaptive immunity and the inflammatory pathway. Typically, adaptive immunological processes pertaining to this context begin with antigen presentation by APCs to naïve helper T cells, a process that activates them via the interaction between a T-cell receptor (TCR), a CD4 glycoprotein, and an antigen-MHC II complex (Class II Major Histocompatibility Complex)67. Activated helpers T cells can then differentiate into either type I helper T cells (Th1), majorly involving Interleukin 12 (IL-12)68, or type II helper T cells (Th2), notedly with the signaling of Interleukin 4 (IL-4)69, which promote cellular and humoral immune responses, respectively. For the former, IFNγ is secreted to promote inflammatory responses that incorporate the release of pro-inflammatory cytokines, whereas, for the latter, IL-4 and Interleukin 5 (IL-5) are secreted to activate antibody production by B lymphocytes70, 71, 72, 73. A homeostatic mechanism has been found to exist between the two; a comparative increase in the Th1 pathway can suppress the Th2 pathway, and vice versa74, 75.

As previously mentioned, the cytokine storm, an excessive release of pro-inflammatory cytokines, is harmful and often contributes to deterioration and death. Therefore, one would surmise that a disproportionate Th1 inflammatory response and an accompanying skewness in the Th1/Th2 ratio could potentially entail a lethal or, at least, devastating cytokine storm54, 76; this is where Vitamin D’s immunomodulatory role becomes highly relevant.

According to research data, 1,25(OH)₂D promotes the differentiation of naïve T cells into Th1 cells via increases in the amounts of GATA-3 and STAT6, which are transcription factors integral to the differentiation pathway77. Furthermore, the active steroid also inhibits IFNγ release while increasing IL-4 secretion78. Both of these effects contribute to the shift in the direction of T cells differentiation towards Th2, decreasing the amount of both Th1 cells and the potentially problematic pro-inflammatory cytokines they produce79. Moreover, 1,25(OH)₂D can also induce the differentiation of naïve T cells into regulatory T cells (Treg) responsible for the restraint of Th1 cells either by upregulating Foxp3, a crucial protein in the differentiation process or by manipulating with a cluster of differentiation (CD) molecules on the surface of dendritic cells, one of whose functions is to foster the development of Tregs80, 81. The totality of this helps to modulate the inflammatory pathway and safeguard the body against disease pathologies82.

One of the most critical reasons why the Renin-Angiotensin System (RAS) bears so much relevance in the topic of vitamin D is that COVID-19 pivots around the SARS-CoV-2’s infection mechanism.

Typically, the RAS acts to maintain the homeostasis of blood pressure, as well as blood electrolytes83. Its ultimate and most bioactive effector, the octapeptide Angiotensin II (Ang-II), usually binds with type I angiotensin receptors (AT1Rs) to attain the goal of increasing BP through vasoconstriction and the secretion of Aldosterone (which stimulates renal Na⁺ absorption and thus more water retention). However, the binding can also have adverse effects as it promotes inflammation, platelet aggregation, production of mitotic agents, and ROS synthesis (which diminishes the availability of nitric oxide, upon which the functionality of endothelial cells is dependent)84. These effects can morph into deleterious conditions, such as thrombosis, fibrosis, oxidative stress, and endothelial dysfunction84, 85.

Alternatively, Ang-II can also interact with Angiotensin-converting Enzyme 2 (ACE2), which cleaves away the phenylalanine at its carboxy terminus, turning it into Angiotensin–(1-7), which can also be produced from the sequential cleavages of Ang-II’s precursor, the decapeptide Angiotensin I (Ang-I), by Angiotensin-converting Enzyme (ACE) and ACE2, respectively83. Angiotensin-(1-7) then binds with the G protein-coupled receptor (GPCR) Mas, leading to effects opposite to those stemming from the interaction between Ang-II and AT1R—vasodilation, anti-fibrosis, anti-inflammation, and vascular protection, just to name a few86.

Unfortunately, SARS-CoV-2’s mechanism of entry into human cells happens to hinge upon ACE2. After the human serine-protease TMPRSS2 enzyme primes its spike proteins, they bind with ACE2 on the human cell membrane, beginning entry by receptor-mediated endocytosis87. As the virus proliferates, the binding of ACE2 becomes more extensive, and the availability of ACE2 plunges in the short term, ensured by the enzyme’s downregulation in the long term, decreasing Ang-II's conversion into Angiotensin-(1-7)88. This shifts the balance of the RAS greatly in that less binding between Angiotensin-(1-7) and Mas would be incurred, whereas the binding between Ang-II and AT1R would be elevated89. These interactions prove to be of great detriment for COVID-19 patients. The former has been described to protect the body against pulmonary fibrosis, acute lung injury, and fibrosis90, 91. The latter is where Vitamin D has profound effects upon alleviating the consequences of SARS-CoV-2 infection.

The steroidal hormone has been indicated to increase the expression of ACE2 and ergo, the activity of the ACE2/Angiotensin-(1-7)/Mas axis92, 93. This consequently suppresses the potentially pernicious ACE/Ang-II/AT1R axis and moderates the body’s inflammatory response, palliating acute lung injury and precluding multiple organ damage that could be precipitated by COVID-1994, 95.

While the aforementioned association between Vitamin D deficiency and either risk of COVID-19 contraction or severe outcomes, corroborated by all the germane mechanisms detailed above, might tantalize one to believe that Vitamin D supplementation can translate into protection against SARS-CoV-2, the reality is yet too complex for such a straightforward notion.

However, data from some research studies seem to substantiate the notion. For example, a meta-analysis96 found lower intensive care unit (ICU) admissions in COVID-19 patients supplemented with Vitamin D. One study97 also observed a decrease in disease severity, mortality rate, and serum level of markers of inflammation in Vitamin D-supplemented patients. Moreover, another study98 reported that high-dose Vitamin D supplementation aided the body’s clearance of SARS-CoV-2 and helped mildly symptomatic and asymptomatic individuals infected with COVID-19 to become COVID-19-negative. These findings are in line with that of a preceding study99 which reported that Vitamin D supplementation helped protect against acute respiratory infections.

Nevertheless, the current evidence is insufficient to conclude that Vitamin D supplements are substantively helpful against COVID-19 or for suggesting Vitamin D supplementation as a hedge against the disease. Furthermore, some studies would digress from such a conclusion. One100, for instance, found no significant difference in the length of hospitalization between patients given Vitamin D supplements and those given placebo. Another study101, albeit not precisely concerning COVID-19, also reported no reduction in pneumonia risk and an even elevated risk of pneumonia recurrence from taking oral Vitamin D supplements. Due to this reason, there remains more investigations to be executed and queries to be answered.

Multiple clinical studies and circumstantial observations have correlated Vitamin D levels and COVID-19 infection, severity, and mortality. This correlation could be rationalized by an insight into the multi-faceted roles of Vitamin D in the physiology of the human immune and endocrine systems.

On the immunological side, the steroidal hormone’s active form, 1,25(OH)₂D, can promote the secretion of antimicrobial peptides like Cathelicidins and BD-2, responsible for thwarting viral replication and achieving viral clearance. Vitamin D can also stimulate autophagy by upregulating Beclin1 and downregulating mTOR, leading to antigen presentation and subsequent activation of the type I INF antiviral pathway. It can also maintain cellular junctions, especially those in the respiratory epithelia, via regulation of Claudins, Occludin, and ZO-1, among a host of junction proteins, thus preserving the integrity of the body’s barriers and reducing their permeability against pathogens. Moreover, it is responsible for fostering naïve T cells into Th2 cells functioning in humoral immunity and inhibiting the inflammatory Th1 pathway, an immunomodulatory role that helps avert the calamitous cytokine storm. Meanwhile, on the endocrinological side, the vitamin can promote the activity of ACE2 and, thus, the binding between Angiotensin-(1-7) and Mas receptors, repressing that between Ang-II and AT1R could result in fibrosis and acute lung injury.

This whole prospective may appear promising and generate an incentive for Vitamin D supplementation as a protective measure against COVID-19. Yet, the current information pool is inadequate for one to suggest such a supplementation regimen. There remains a great deal of unclarity, and hence, a considerable necessity for even more thorough research in the future.

1,25(OH)2D: 1,25-dihydroxyvitamin D

25-OHD: 25-hydroxyvitamin D

ACE2: Angiotensin-converting Enzyme 2

ACE: Angiotensin-converting Enzyme

ALI: Acute Lung Injury

Ang-II: Angiotensin II

APC: Antigen-presenting Cell

ARDS: Acute Respiratory Distress Syndrome

AT1R: Type I Angiotensin Receptor

BD-2: β-defensin 2

CD: Cluster of Differentiation

COVID-19: Coronavirus Disease 2019

CYP27B1: 1α-hydroxylase

GPCR: G protein-coupled receptor

IL-1: Interleukin 1

IL-4: Interleukin 4

IL-5: Interleukin 5

IL-6: Interleukin 6

IL-8: Interleukin 8

IL-10: Interleukin 10

IL-12: Interleukin 12

INF: Interferon

INF-γ: Interferon Gamma

MERS: Middle East Respiratory Syndrome

MHC II: Class II Major Histocompatibility Complex

mTOR: mammalian target of Rapamycin

NET: Neutrophil Extracellular Trap

PRR: Pattern Recognition Receptor

PTH: Parathyroid Hormone

RAS: Renin-Angiotensin System

ROS: Reactive Oxygen Species

SARS: Severe Acute Respiratory Syndrome

SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2

TCR: T-cell Receptor

Th1: Type I Helper T cells

Th2: Type II Helper T cells

TNF-α: Tumor Necrosis Factor Alpha

Treg: Regulatory T cells

VDR: Vitamin D Receptor

None

Not applicable.

None

Not applicable

Not applicable

Not applicable

The author declares that he/she has no competing interests.

Hu B. Guo H. Zhou P. Shi Z.L. Characteristics of SARS-CoV-2 and COVID-19 Nat Rev Microbiol 2021 19 3 141 54 1740-1534 10.1038/s41579-020-00459-7 33024307 Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity J Infect Public Health 2020 13 10 1373 80 1876-035X 10.1016/j.jiph.2020.06.021 32605780 Aranow C. Vitamin D and the immune system J Investig Med 2011 59 6 881 6 1708-8267 10.2310/JIM.0b013e31821b8755 21527855 Prietl B. Treiber G. Pieber T.R. Amrein K. Vitamin D and immune function Nutrients 2013 5 7 2502 21 2072-6643 10.3390/nu5072502 23857223 Bivona G. Agnello L. Ciaccio M. The immunological implication of the new vitamin D metabolism Cent Eur J Immunol 2018 43 3 331 4 1426-3912 10.5114/ceji.2018.80053 30588177 Martens P.J. Gysemans C. Verstuyf A. Mathieu A.C. Vitamin D's Effect on Immune Function Nutrients 2020 12 5 1248 2072-6643 10.3390/nu12051248 32353972 Goldsmith J.R. Vitamin D as an Immunomodulator: Risks with Deficiencies and Benefits of Supplementation Healthcare (Basel) 2015 3 2 219 32 2227-9032 10.3390/healthcare3020219 27417758 Youssef D.A. Miller C.W. El-Abbassi A.M. Cutchins D.C. Cutchins C. Grant W.B. Antimicrobial implications of vitamin D Dermatoendocrinol 2011 3 4 220 9 1938-1980 10.4161/derm.3.4.15027 22259647 Gunville C.F. Mourani P.M. Ginde A.A. The role of vitamin D in prevention and treatment of infection Inflamm Allergy Drug Targets 2013 12 4 239 45 2212-4055 10.2174/18715281113129990046 23782205 Dankers W. Colin E.M. van Hamburg J.P. Lubberts E. Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential Front Immunol 2017 7 697 1664-3224 10.3389/fimmu.2016.00697 28163705 Infante M. Ricordi C. Sanchez J. Clare-Salzler M.J. Padilla N. Fuenmayor V. Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes Nutrients 2019 11 9 2185 2072-6643 10.3390/nu11092185 31514368 Meltzer D.O. Best T.J. Zhang H. Vokes T. Arora V. Solway J. Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence MedRxiv 2020 10.1101/2020.05.08.20095893 McCall B. Vitamin D Deficiency in COVID-19 Quadrupled Death Rate [Internet]. Medscape. Medscape; 2020 [cited 2021Apr29]. Available from: https://www.medscape.com/viewarticle/942497 Ahmad A. Heumann C. Ali R. Oliver T. Vitamin D levels in 19 European Countries & COVID-19 Mortality over 10 months. 2021 Daneshkhah A. Agrawal V. Eshein A. Subramanian H. Roy H.K. Backman V. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. 2020 Smet D. De Smet K. De Herroelen P. Gryspeerdt S. Martens G.A. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics MedRxiv 2020 10.1101/2020.05.01.20079376 Ilie P.C. 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 8 1720-8319 10.1007/s40520-020-01570-8 32377965 Hovsepian S. Amini M. Aminorroaya A. Amini P. Iraj B. Prevalence of vitamin D deficiency among adult population of Isfahan City, Iran J Health Popul Nutr 2011 29 2 149 55 1606-0997 10.3329/jhpn.v29i2.7857 21608424 Hansdottir S. Monick M.M. Lovan N. Powers L. Gerke A. Hunninghake G.W. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state J Immunol 2010 184 2 965 74 1550-6606 10.4049/jimmunol.0902840 20008294 Ginde A.A. Mansbach J.M. Camargo C.A. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey Arch Intern Med 2009 169 4 384 90 1538-3679 10.1001/archinternmed.2008.560 19237723 Sabetta J.R. DePetrillo P. Cipriani R.J. Smardin J. Burns L.A. Landry M.L. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults PLoS One 2010 5 6 e11088 1932-6203 10.1371/journal.pone.0011088 20559424 Laaksi I. Ruohola J.P. Tuohimaa P. Auvinen A. Haataja R. Pihlajamäki H. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men Am J Clin Nutr 2007 86 3 714 7 0002-9165 10.1093/ajcn/86.3.714 17823437 Cannell J.J. Vieth R. Umhau J.C. Holick M.F. Grant W.B. Madronich S. Epidemic influenza and vitamin D Epidemiol Infect 2006 134 6 1129 40 0950-2688 10.1017/S0950268806007175 16959053 Bodnar L.M. Krohn M.A. Simhan H.N. Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy J Nutr 2009 139 6 1157 61 1541-6100 10.3945/jn.108.103168 19357214 Rodríguez M. Daniels B. Gunawardene S. Robbins G.K. High frequency of vitamin D deficiency in ambulatory HIV-Positive patients AIDS Res Hum Retroviruses 2009 25 1 9 14 1931-8405 10.1089/aid.2008.0183 19108690 Wang T.T. Nestel F.P. Bourdeau V. Nagai Y. Wang Q. Liao J. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression J Immunol 2004 173 5 2909 12 0022-1767 10.4049/jimmunol.173.5.2909 15322146 Yim S. Dhawan P. Ragunath C. Christakos S. Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3) J Cyst Fibros 2007 6 6 403 10 1569-1993 10.1016/j.jcf.2007.03.003 17467345 Bilezikian J.P. Bikle D. Hewison M. Lazaretti-Castro M. Formenti A.M. Gupta A. Mechanism in endocrinology: vitamin D and COVID-19 Eur J Endocrinol 2020 183 5 133 47 1479-683X 10.1530/EJE-20-0665 32755992 Armas L.A. Vitamin D, infections and immune-mediated diseases Int J Clin Rheumatol 2009 4 1 89 103 1758-4272 10.2217/17584272.4.1.89 Hansdottir S. Monick M.M. Hinde S.L. Lovan N. Look D.C. Hunninghake G.W. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense J Immunol 2008 181 10 7090 9 1550-6606 10.4049/jimmunol.181.10.7090 18981129 Ramanathan B. Davis E.G. Ross C.R. Blecha F. Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity Microbes Infect 2002 4 3 361 72 1286-4579 10.1016/S1286-4579(02)01549-6 11909747 Tripathi S. Tecle T. Verma A. Crouch E. White M. Hartshorn K.L. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins J Gen Virol 2013 94 Pt 1 40 9 1465-2099 10.1099/vir.0.045013-0 23052388 Sousa F.H. Casanova V. Findlay F. Stevens C. Svoboda P. Pohl J. Cathelicidins display conserved direct antiviral activity towards rhinovirus Peptides 2017 95 76 83 1873-5169 10.1016/j.peptides.2017.07.013 28764966 Barlow P.G. Svoboda P. Mackellar A. Nash A.A. York I.A. Pohl J. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37 PLoS One 2011 6 10 e25333 1932-6203 10.1371/journal.pone.0025333 22031815 Barlow P.G. Findlay E.G. Currie S.M. Davidson D.J. Antiviral potential of cathelicidins Future Microbiol 2014 9 1 55 73 1746-0921 10.2217/fmb.13.135 24328381 Selsted M.E. Ouellette A.J. Mammalian defensins in the antimicrobial immune response Nat Immunol 2005 6 6 551 7 1529-2908 10.1038/ni1206 15908936 Ganz T. Defensins: antimicrobial peptides of innate immunity Nat Rev Immunol 2003 3 9 710 20 1474-1733 10.1038/nri1180 12949495 Hazlett L. Wu M. Defensins in innate immunity Cell Tissue Res 2011 343 1 175 88 1432-0878 10.1007/s00441-010-1022-4 20730446 Kim J. Yang Y.L. Jang S.H. Jang Y.S. Human β-defensin 2 plays a regulatory role in innate antiviral immunity and is capable of potentiating the induction of antigen-specific immunity Virol J 2018 15 1 124 1743-422X 10.1186/s12985-018-1035-2 30089512 Liu P.T. Stenger S. Li H. Wenzel L. Tan B.H. Krutzik S.R. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response Science 2006 311 5768 1770 3 1095-9203 10.1126/science.1123933 16497887 Adams J.S. Rafison B. Witzel S. Reyes R.E. Shieh A. Chun R. Regulation of the extrarenal CYP27B1-hydroxylase J Steroid Biochem Mol Biol 2014 144 22 7 1879-1220 10.1016/j.jsbmb.2013.12.009 24388948 Zhang Y-guo Wu S, Sun J. Vitamin D, vitamin D receptor and tissue barriers Tissue Barriers 2013 1 1 2168-8362 Zhang Y.G. Wu S. Lu R. Zhou D. Zhou J. Carmeliet G. Tight junction CLDN2 gene is a direct target of the vitamin D receptor Sci Rep 2015 5 1 10642 2045-2322 10.1038/srep10642 26212084 Stio M. Retico L. Annese V. Bonanomi A.G. Vitamin D regulates the tight-junction protein expression in active ulcerative colitis Scand J Gastroenterol 2016 51 10 1193 9 1502-7708 10.1080/00365521.2016.1185463 27207502 Fujita H. Sugimoto K. Inatomi S. Maeda T. Osanai M. Uchiyama Y. Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes Mol Biol Cell 2008 19 5 1912 21 1939-4586 10.1091/mbc.e07-09-0973 18287530 Elizondo R.A. Yin Z. Lu X. Watsky M.A. Effect of vitamin D receptor knockout on cornea epithelium wound healing and tight junctions Invest Ophthalmol Vis Sci 2014 55 8 5245 51 1552-5783 10.1167/iovs.13-13553 25061117 Kong J. Zhang Z. Musch M.W. Ning G. Sun J. Hart J. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier Am J Physiol Gastrointest Liver Physiol 2008 294 1 208 16 0193-1857 10.1152/ajpgi.00398.2007 17962355 Chen H. Lu R. Zhang Y.G. Sun J. Vitamin D Receptor Deletion Leads to the Destruction of Tight and Adherens Junctions in Lungs Tissue Barriers 2018 6 4 1 13 2168-8370 10.1080/21688370.2018.1540904 30409076 Shi Y.Y. Liu T.J. Fu J.H. Xu W. Wu L.L. Hou A.N. Vitamin D/VDR signaling attenuates lipopolysaccharide induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier Mol Med Rep 2016 13 2 1186 94 1791-3004 10.3892/mmr.2015.4685 26675943 Abdel-Mohsen M.A. El-Braky A.A. Ghazal A.A. Shamseya M.M. Autophagy, apoptosis, vitamin D, and vitamin D receptor in hepatocellular carcinoma associated with hepatitis C virus Medicine (Baltimore) 2018 97 12 e0172 1536-5964 10.1097/MD.0000000000010172 29561429 Wang J. Lian H. Zhao Y. Kauss M.A. Spindel S. Vitamin D3 induces autophagy of human myeloid leukemia cells J Biol Chem 2008 283 37 25596 605 0021-9258 10.1074/jbc.M801716200 18628207 Choi Y. Bowman J.W. Jung J.U. Autophagy during viral infection - a double-edged sword Nat Rev Microbiol 2018 16 6 341 54 1740-1534 10.1038/s41579-018-0003-6 29556036 Mao J. Lin E. He L. Yu J. Tan P. Zhou Y. Autophagy and viral infection Adv Exp Med Biol 2019 1209 55 78 0065-2598 10.1007/978-981-15-0606-2_5 31728865 Fajgenbaum D.C. June C.H. Cytokine Storm N Engl J Med 2020 383 23 2255 73 1533-4406 10.1056/NEJMra2026131 33264547 Hojyo S. Uchida M. Tanaka K. Hasebe R. Tanaka Y. Murakami M. How COVID-19 induces cytokine storm with high mortality Inflamm Regen 2020 40 1 37 1880-9693 10.1186/s41232-020-00146-3 33014208 Moore J.B. June C.H. Cytokine release syndrome in severe COVID-19 Science 2020 368 6490 473 4 1095-9203 10.1126/science.abb8925 32303591 Cron R.Q. COVID-19 cytokine storm: targeting the appropriate cytokine Lancet Rheumatol 2021 3 4 e236 7 2665-9913 10.1016/S2665-9913(21)00011-4 33655221 Channappanavar R. Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Semin Immunopathol 2017 39 5 529 39 1863-2300 10.1007/s00281-017-0629-x 28466096 Tang L. Yin Z. Hu Y. Mei H. Controlling Cytokine Storm Is Vital in COVID-19 Front Immunol 2020 11 570993 1664-3224 10.3389/fimmu.2020.570993 33329533 Shimabukuro-Vornhagen A. Gödel P. Subklewe M. Stemmler H.J. Schlö\sser H.A. Schlaak M. Cytokine release syndrome J Immunother Cancer 2018 6 1 56 2051-1426 10.1186/s40425-018-0343-9 29907163 Wong C.K. Lam C.W. Wu A.K. Ip W.K. Lee N.L. Chan I.H. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome Clin Exp Immunol 2004 136 1 95 103 0009-9104 10.1111/j.1365-2249.2004.02415.x 15030519 Zhang Y. Li J. Zhan Y. Wu L. Yu X. Zhang W. Analysis of serum cytokines in patients with severe acute respiratory syndrome Infect Immun 2004 72 8 4410 5 0019-9567 10.1128/IAI.72.8.4410-4415.2004 15271897 Zhang J.M. An J. Cytokines, inflammation, and pain Int Anesthesiol Clin 2007 45 2 27 37 0020-5907 10.1097/AIA.0b013e318034194e 17426506 Vardhana S.A. Wolchok J.D. The many faces of the anti-COVID immune response J Exp Med 2020 217 6 e20200678 1540-9538 10.1084/jem.20200678 32353870 Meftahi G.H. Jangravi Z. Sahraei H. Bahari Z. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of inflame-aging Inflamm Res 2020 69 9 825 39 1420-908X 10.1007/s00011-020-01372-8 32529477 Bonaventura A. Vecchié A. Dagna L. Martinod K. Dixon D.L. Van Tassell B.W. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19 Nat Rev Immunol 2021 21 5 319 29 1474-1741 10.1038/s41577-021-00536-9 33824483 Luckheeram R.V. Zhou R. Verma A.D. Xia B. CD4+ T cells: differentiation and functions Clin Dev Immunol 2012 2012 925135 1740-2530 10.1155/2012/925135 22474485 Trinchieri G. Pflanz S. Kastelein R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses Immunity 2003 19 5 641 4 1074-7613 10.1016/S1074-7613(03)00296-6 14614851 Chen L. Grabowski K.A. Xin J.P. Coleman J. Huang Z. Espiritu B. IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils J Immunol 2004 172 4 2059 66 0022-1767 10.4049/jimmunol.172.4.2059 14764670 Paul W.E. Seder R.A. Lymphocyte responses and cytokines Cell 1994 76 2 241 51 0092-8674 10.1016/0092-8674(94)90332-8 7904900 Berger A. Th1 and Th2 responses: what are they? BMJ 2000 321 7258 424 0959-8138 10.1136/bmj.321.7258.424 10938051 Mosmann T.R. Coffman R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties Annu Rev Immunol 1989 7 1 145 73 0732-0582 10.1146/annurev.iy.07.040189.001045 2523712 Abbas A.K. Murphy K.M. Sher A. Functional diversity of helper T lymphocytes Nature 1996 383 6603 787 93 0028-0836 10.1038/383787a0 8893001 Kidd Parris Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease Alternative medicine review : a journal of clinical therapeutic 2003 8 3 223 46 Eden W. van Zee R. van der Kooten P. van Berlo S.E. Cobelens P.M. Kavelaars A. Balancing the immune system: Th1 and Th2 Annals of the Rheumatic Diseases 2002 61 Supplement 2 25 28 Silva R. Morgado J.M. Freitas A. Couceiro A. Orfao A. Regateiro F. Influence of pro- and anti-inflammatory cytokines in Th1 polarization after allogeneic stimulation Int J Biomed Sci 2005 1 1 46 52 1550-9702 23674953 Cantorna M.T. Snyder L. Lin Y.D. Yang L. Vitamin D and 1,25(OH)2D regulation of T cells Nutrients 2015 7 4 3011 21 2072-6643 10.3390/nu7043011 25912039 Bivona G. Agnello L. Ciaccio M. Vitamin D and Immunomodulation: Is It Time to Change the Reference Values? Ann Clin Lab Sci 2017 47 4 508 10 1550-8080 28801380 Kang S.W. Kim S.H. Lee N. Lee W.W. Hwang K.A. Shin M.S. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region J Immunol 2012 188 11 5276 82 1550-6606 10.4049/jimmunol.1101211 22529297 Adorini L. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes Ann N Y Acad Sci 2003 987 1 258 61 0077-8923 10.1111/j.1749-6632.2003.tb06057.x 12727648 Cantorna M.T. Munsick C. Bemiss C. Mahon B.D. 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease J Nutr 2000 130 11 2648 52 0022-3166 10.1093/jn/130.11.2648 11053501 Fountain J.H. Lappin S.L. Physiology, Renin Angiotensin System StatPearls Publishing Treasure Island (FL) 2021 Dandona P. Dhindsa S. Ghanim H. Chaudhuri A. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade J Hum Hypertens 2007 21 1 20 7 0950-9240 10.1038/sj.jhh.1002101 17096009 Murphy A.M. Wong A.L. Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis Fibrogenesis & Tissue Repair 2015 8 7 10.1186/s13069-015-0023-z Santos R.A. Simoes e Silva A.C. Maric C. Silva D.M. Machado R.P. de Buhr I. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas Proc Natl Acad Sci USA 2003 100 14 8258 63 0027-8424 10.1073/pnas.1432869100 12829792 Hoffmann M. Kleine-Weber H. Schroeder S. Krüger N. Herrler T. Erichsen S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Cell 2020 181 2 1097-4172 10.1016/j.cell.2020.02.052 32142651 Silhol F. Sarlon G. Deharo J.C. Vaisse B. Downregulation of ACE2 induces overstimulation of the renin-angiotensin system in COVID-19: should we block the renin-angiotensin system? Hypertens Res 2020 43 8 854 6 1348-4214 10.1038/s41440-020-0476-3 32439915 Gheblawi M. Wang K. Viveiros A. Nguyen Q. Zhong J.C. Turner A.J. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2 Circ Res 2020 126 10 1456 74 1524-4571 10.1161/CIRCRESAHA.120.317015 32264791 Bhalla V. Blish C.A. South A.M. A historical perspective on ACE2 in the COVID-19 era J Hum Hypertens 2020 1476-5527 10.1038/s41371-020-00459-3 Zhang B.N. Xu H. Gao X.M. Zhang G.Z. Zhang X. Yang F. Protective Effect of Angiotensin (1-7) on Silicotic Fibrosis in Rats Biomed Environ Sci 2019 32 6 419 26 2214-0190 31262387 Malek Mahdavi A. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: implications for a potential treatment for COVID-19 Rev Med Virol 2020 30 5 e2119 1099-1654 10.1002/rmv.2119 32584474 McLachlan C.S. The angiotensin-converting enzyme 2 (ACE2) receptor in the prevention and treatment of COVID-19 are distinctly different paradigms Clin Hypertens 2020 26 1 14 2056-5909 10.1186/s40885-020-00147-x 32685191 Xu J. Yang J. Chen J. Luo Q. Zhang Q. Zhang H. Vitamin D alleviates lipopolysaccharide‑induced acute lung injury via regulation of the renin‑angiotensin system Mol Med Rep 2017 16 5 7432 8 1791-3004 10.3892/mmr.2017.7546 28944831 Aygun H. Vitamin D can prevent COVID-19 infection-induced multiple organ damage Naunyn Schmiedebergs Arch Pharmacol 2020 393 7 1157 60 1432-1912 10.1007/s00210-020-01911-4 32451597 Shah K. Saxena D. Mavalankar D. Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis QJM: An International Journal of Medicine 2021 114 3 175 181 https://doi.org/10.1093/qjmed/hcab009 Nikniaz L. Akbarzadeh M.A. Hosseinifard H. Hosseini M.-S. The impact of vitamin D supplementation on mortality rate and clinical outcomes of COVID-19 patients: A systematic review and meta-analysis MedRxiv 2021 10.1101/2021.01.04.21249219 Rastogi A. Bhansali A. Khare N. Suri V. Yaddanapudi N. Sachdeva N. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study) Postgrad Med J 2020 1469-0756 10.1136/postgradmedj-2020-139065 Martineau A.R. Jolliffe D.A. Hooper R.L. Greenberg L. Aloia J.F. Bergman P. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data BMJ 2017 356 i6583 1756-1833 10.1136/bmj.i6583 28202713 Murai I.H. Fernandes A.L. Sales L.P. Pinto A.J. Goessler K.F. Duran C.S. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial JAMA 2021 325 11 1053 60 1538-3598 10.1001/jama.2020.26848 33595634 Sloka S. Silva C. Wang J. Yong V.W. Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism J Neuroinflammation 2011 8 1 56 1742-2094 10.1186/1742-2094-8-56 21605467 Manaseki-Holland S. Maroof Z. Bruce J. Mughal M.Z. Masher M.I. Bhutta Z.A. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial Lancet 2012 379 9824 1419 27 1474-547X 10.1016/S0140-6736(11)61650-4 22494826