Vitamin D and immuno-pathology of COVID-19: many interactions but uncertain therapeutic benefits

References

• WHO Weekly Epidemiological and Operational updates. 2020. [cited 2020 Dec 1]. Available from: https://www.who.int/publications/m/item/weekly-epidemiological-update—1-december-2020
   Google Scholar
• Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
   PubMed Web of Science ®Google Scholar
• Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565–574.
   PubMed Web of Science ®Google Scholar
• Sardar R, Satish D, Birla S, et al. Integrative analyses of SARS-CoV-2 genomes from different geographical locations reveal unique features potentially consequential to host-virus interaction, pathogenesis and clues for novel therapies. Heliyon. 2020;6(9):e04658.
   PubMed Web of Science ®Google Scholar
• Peiris JSM, Yuen KY, Osterhaus ADME, et al. The severe acute respiratory syndrome. N Engl J Med. 2003;349(25):2431–2441.
   PubMed Web of Science ®Google Scholar
• Fehr AR, Channappanavar R, Perlman S. Middle east respiratory syndrome: emergence of a pathogenic human coronavirus. Annu Rev Med. 2017;68(1):387–399.
   PubMedGoogle Scholar
• Sharif-Yakan A, Kanj SS. Emergence of MERS-CoV in the Middle East: origins, transmission, treatment, and perspectives. PLoS Pathog. 2014;10(12):e1004457.
   PubMed Web of Science ®Google Scholar
• Raoult D, Zumla A, Locatelli F, et al. Coronavirus infections: epidemiological, clinical and immunological features and hypotheses. Cell Stress. 2020;4(4):66–74.
   PubMed Web of Science ®Google Scholar
• Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433.
   PubMed Web of Science ®Google Scholar
• Chakrabarti SS, Kaur U, Banerjee A, et al. COVID-19 in India: are biological and environmental factors helping to stem the incidence and severity? Aging Dis. 2020;11(3):480–488.
   PubMed Web of Science ®Google Scholar
• Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
   PubMed Web of Science ®Google Scholar
• Huang W, Berube J, McNamara M, et al. Lymphocyte subset counts in COVID-19 patients: a meta-analysis. Cytometry. 2020;97(8):772–776.
   PubMedGoogle Scholar
• Sanyaolu A, Okorie C, Marinkovic A, et al. Comorbidity and its impact on patients with COVID-19. SN Compr Clin Med. 2020;1–8. DOI:https://doi.org/10.1007/s42399-020-00363-4.
   Google Scholar
• Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID-19: a Single health system study. J Am Coll Cardiol. 2020;76(16):1815-1826.
   Web of Science ®Google Scholar
• Madjid M, Safavi-Naeini P, Solomon SD, et al. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. 2020;5(7):831–840.
   PubMed Web of Science ®Google Scholar
• Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–1418.
   PubMed Web of Science ®Google Scholar
• Fogarty H, Townsend L, Cheallaigh CN, et al. COVID19 coagulopathy in Caucasian patients. Br J Haematol. 2020;189(6):1044–1049.
   PubMed Web of Science ®Google Scholar
• Calabrese F, Pezzuto F, Fortarezza F, et al. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European Pulmonary Pathologists. Virchows Arch. 2020;477(3):359–372.
   PubMed Web of Science ®Google Scholar
• Borczuk AC, Salvatore SP, Seshan SV, et al. COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City. Mod Pathol. 2020;33(11):2156–2168.
   PubMed Web of Science ®Google Scholar
• Tay MZ, Poh CK, Rénia L, et al. The Trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363–374.
   PubMed Web of Science ®Google Scholar
• Vaduganathan M, Vardeny O, Michel T, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382(17):1653–1659.
   PubMed Web of Science ®Google Scholar
• Kaur U, Acharya K, Mondal R, et al. Should ACE2 be given a chance in COVID-19 therapeutics: a semi-systematic review of strategies enhancing ACE2. Eur J Pharmacol. 2020;887:173545.
   PubMed Web of Science ®Google Scholar
• Jakovac H. COVID-19 and vitamin D—Is there a link and an opportunity for intervention? Endocrinol Metab. 2020;318(5):589.
   Google Scholar
• Slominski AT, Slominski RM, Goepfert PA, et al. Can vitamin D prevent or manage COVID-19 illness? Am J Physiol Endocrinol Metab. 2020;319(2):455–457.
   PubMed Web of Science ®Google Scholar
• Machhi J, Herskovitz J, Senan AM, et al. The Natural History, pathobiology, and clinical manifestations of SARS-CoV-2 infections. J Neuroimmune Pharmacol. 2020;15(3):359–386.
   PubMed Web of Science ®Google Scholar
• Johnson KD, Harris C, Cain JK, et al. Pulmonary and extra-pulmonary clinical manifestations of COVID-19. Front Med. 2020;7:526.
   Web of Science ®Google Scholar
• Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARSCoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280.
   PubMed Web of Science ®Google Scholar
• Wang JJ, Edin ML, Zeldin DC, et al. Good or bad: application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities. Pharmacol Ther. 2020;215:107628.
   PubMed Web of Science ®Google Scholar
• Kaur U, Chakrabarti SS, Ojha B, et al. Targeting host cell proteases to prevent SARS-CoV-2 invasion. Curr Drug Targets. 2021;22(2):2.
   PubMed Web of Science ®Google Scholar
• Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323(18):1843–1844.
   PubMed Web of Science ®Google Scholar
• Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J. 2020;55(4):2000607.
   PubMed Web of Science ®Google Scholar
• Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: a review. J Clim. 2020;215:108427.
   Google Scholar
• Xu CC, Ruan XZ, Chen XQ, et al. CT-based staging and prognosis of novel coronavirus (COVID-19) pneumonia: correlation with blood glucose levels. Eur Rev Med Pharmacol Sci. 2020;24(24):13056–13061.
   PubMed Web of Science ®Google Scholar
• Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–407.
   PubMed Web of Science ®Google Scholar
• Cordon-Cardo C, Pujadas E, Wajnberg A, et al. COVID-19: staging of a new disease. Cancer Cell. 2020;38(5):594–597.
   PubMed Web of Science ®Google Scholar
• World Health Organization. 2020. Clinical management of COVID-19: interim guidance, 2020. World Health Organization. [cited 2021 Feb 10]. Available from: https://apps.who.int/iris/handle/10665/332196.
   Google Scholar
• Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by Vitamin D. Nutr. 2015;7(6):4240–4270.
   Google Scholar
• Katze MG, Fornek JL, Palermo RE, et al. Innate immune modulation by RNA viruses: emerging insights from functional genomics. Nat Rev Immunol. 2008;8(8):644–654.
   PubMed Web of Science ®Google Scholar
• Katze MG, He Y, Gale M. Viruses and interferon: a fight for supremacy. Nat Rev Immunol. 2002;2(9):675–687.
   PubMed Web of Science ®Google Scholar
• Unterholzner L, Almine JF. Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors. Immunol. 2018;156(3):217–227.
   PubMed Web of Science ®Google Scholar
• Alcami A. Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol. 2003;3(1):36–50.
   PubMed Web of Science ®Google Scholar
• Hartman AL, Towner JS, Nichol STA. C-terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus. Virology. 2004;328(2):177–184.
   PubMed Web of Science ®Google Scholar
• Kash JC, Muhlberger E, Carter V, et al. Global suppression of the host antiviral response by Ebola- and Marburgviruses: increased antagonism of the type I interferon response is associated with enhanced virulence. J Virol. 2006;80(6):3009–3020.
   PubMed Web of Science ®Google Scholar
• Li G, Fan Y, Lai Y, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424–432.
   PubMed Web of Science ®Google Scholar
• Wang YT, Landeras-Bueno S, Hsieh LE, et al. Spiking pandemic potential: structural and immunological aspects of SARS-CoV-2. Trends Microbiol. 2020;28(8):605–618.
   PubMed Web of Science ®Google Scholar
• Tang Y, Liu J, Zhang D, et al. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol. 2020;11:1708.
   PubMed Web of Science ®Google Scholar
• Garcia LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.
   PubMed Web of Science ®Google Scholar
• Birra D, Benucci M, Landolfi L, et al. COVID 19: a clue from innate immunity. Immunol Res. 2020;68(3):161–168.
   PubMed Web of Science ®Google Scholar
• Amor S, Fernandez Blanco L, Baker D. Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage. Clin Exp Immunol. 2020;202(2):193–209.
   PubMed Web of Science ®Google Scholar
• Fung SY, Yuen KS, Ye ZW, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020;9(1):558–570.
   PubMed Web of Science ®Google Scholar
• Pellegrini S, Uze G. An old cytokine against a new virus? J Interferon Cytokine Res. 2020;40(8):425–428.
   PubMed Web of Science ®Google Scholar
• Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(6):355–362.
   PubMed Web of Science ®Google Scholar
• Trouillet-Assant S, Viel S, Gaymard A, et al. Type I IFN immunoprofiling in COVID-19 patients. J Allergy Clin Immunol. 2020;146(1):206–208.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Ren L, Zhang L, et al. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe. 2020;28(6):883–890.
   Google Scholar
• Catanzaro M, Fagiani F, Racchi M, et al. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct Target Ther. 2020;5(1):84. DOI:https://doi.org/10.1038/s41392-020-0191-1
   PubMed Web of Science ®Google Scholar
• Pedersen SV, Ho Y-C. SARS-CoV-2: a storm is raging. J Clin Invest. 2020;130(5):2202–2205.
   PubMed Web of Science ®Google Scholar
• Kaur S, Bansal R, Kollimuttathuillam S, et al. The looming storm: blood and cytokines in COVID-19. Blood Rev. 2020;100743. DOI:https://doi.org/10.1016/j.blre.2020.100743.
   Google Scholar
• Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan. China Clin Infect Dis. 2020;71(15):762–768.
   PubMed Web of Science ®Google Scholar
• Varchetta S, Mele D, Oliviero B, et al. Unique immunological profile in patients with COVID-19. Cell Mol Immunol. 2020;1–9. DOI:https://doi.org/10.1038/s41423-020-00557-9.
   Google Scholar
• Xu B, Fan CY, Wang AL, et al. Suppressed T cell-mediated immunity in patients with COVID-19: a clinical retrospective study in Wuhan, China. J Infect. 2020;81(1):51–60.
   PubMed Web of Science ®Google Scholar
• Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol. 2020;11:827.
   PubMed Web of Science ®Google Scholar
• Sun HB, Zhang YM, Huang LG, et al. The changes of the peripheral CD4+ lymphocytes and inflammatory cytokines in patients with COVID-19. PLOS One. 2020;15(9):e0239532.
   PubMed Web of Science ®Google Scholar
• Maucourant C, Filipovic I, Ponzetta A, et al. Natural killer cell immunotypes related to COVID-19 disease severity. Sci Immunol. 2020;5(50):eabd6832.
   PubMed Web of Science ®Google Scholar
• Ni L, Ye F, Cheng ML, et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity. 2020;52(6):971–977.
   PubMed Web of Science ®Google Scholar
• Bert NL, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020;584(7821):457–462.
   PubMed Web of Science ®Google Scholar
• Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020;181(7):1489–1501.
   PubMed Web of Science ®Google Scholar
• Peng Y, Mentzer AJ, Liu G, et al. Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat Immunol. 2020;21(11):1336–1345.
   PubMed Web of Science ®Google Scholar
• Mateus J, Grifoni A, Tarke A, et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. 2020;370(6512):89–94.
   PubMed Web of Science ®Google Scholar
• Mathew D, Giles JR, Baxter AE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science. 2020;369(6508):eabc8511.
   PubMed Web of Science ®Google Scholar
• Wu F, Liu M, Wang A, et al. Evaluating the association of clinical characteristics with neutralizing antibody levels in patients who have recovered from mild COVID-19 in Shanghai, China. JAMA Intern Med. 2020;180(10):1356–1362.
   PubMed Web of Science ®Google Scholar
• Rogers TF, Zhao F, Huang D, et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science. 2020;369(6506):956–963.
   PubMed Web of Science ®Google Scholar
• Liu L, Wang P, Nair MS, et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature. 2020;584(7821):450–456.
   PubMed Web of Science ®Google Scholar
• Robbiani DF, Gaebler C, Muecksch F, et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature. 2020;584(7821):437–442.
   PubMed Web of Science ®Google Scholar
• Nguyen-Contant P, Embong K, Kanagaiah P, et al. S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit. mBio. 2020;11(5):e01991–20.
   PubMed Web of Science ®Google Scholar
• Brouwer PJM, Caniels TG, van der Straten K, et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science. 2020;369(6504):643–650.
   PubMed Web of Science ®Google Scholar
• Jiang F, Yang J, Zhang Y, et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat Rev Cardiol. 2014;11(7):413–426.
   PubMed Web of Science ®Google Scholar
• Groβ S, Jahn C, Cushman S, et al. SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: from basic science to clinical implications. J Mol Cell Cardiol. 2020;144:47–53.
   PubMed Web of Science ®Google Scholar
• Chen LN, Yang XH, Nissen DH, et al. Dysregulated renin-angiotensin system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice. Shock. 2013;40(5):420–429.
   PubMed Web of Science ®Google Scholar
• Wang F, Xia ZF, Chen XL, et al. Angiotensin II type-1 receptor antagonist attenuates LPS-induced acute lung injury. Cytokine. 2009;48(3):246–253.
   PubMed Web of Science ®Google Scholar
• Liu L, Qiu HB, Yang Y, et al. Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat. Arch Biochem Biophys. 2009;481(1):131–136.
   PubMed Web of Science ®Google Scholar
• Zhang J, Wang M, Ding W, et al. The interaction of RAAS inhibitors with COVID-19: current progress, perspective and future. Life Sci. 2020;257:118142.
   PubMed Web of Science ®Google Scholar
• Saha S, Chakrabarti S, Singh PK, et al. Physiological relevance of angiotensin converting enzyme 2 as a metabolic linker and therapeutic implication of mesenchymal stem cells in COVID-19 and Hypertension. Stem Cell Rev Rep. 2020;16(1):1–12.
   PubMedGoogle Scholar
• Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757–760.
   PubMed Web of Science ®Google Scholar
• Pirola CJ, Sookoian S. Estimation of Renin-Angiotensin-Aldosterone-System (RAAS)-Inhibitor effect on COVID-19 outcome: a meta-analysis. J Infection. 2020;81(2):276–281.
   PubMed Web of Science ®Google Scholar
• Jakovac H. COVID-19: is the ACE2 just a foe? Am J Physiol Lung Cell Mol Physiol. 2020;318(5):1025–1026.
   PubMed Web of Science ®Google Scholar
• Jakovac H. COVID-19 and hypertension: is the HSP60 culprit for the severe course and worse outcome? Am J Physiol Heart Circ Physiol. 2020;319(4):793–796.
   PubMed Web of Science ®Google Scholar
• Juwono J, Martinus RD. Does Hsp60 provide a link between mitochondrial stress and inflammation in diabetes mellitus? J Diabetes Rese. 2016;8017571. DOI:https://doi.org/10.1155/2016/8017571
   Google Scholar
• Blagonravov ML, Sklifasovskaya AP, Korshunova AY, et al. Heat Shock Protein HSP60 in left ventricular cardiomyocytes of hypertensive rats with and without insulin-dependent diabetes mellitus. Bull Exp Biol Med. 2020;170(1):10–14.
   PubMed Web of Science ®Google Scholar
• Nicholson AG, Osborn M, Devaraj A, et al. COVID‐19 related lung pathology: old patterns in new clothing? Histopathology. 2020;77(2):169–172.
   PubMed Web of Science ®Google Scholar
• Carsana L, Sonzogni A, Nasr A, et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet. 2020;20(10):1135–1140.
   Web of Science ®Google Scholar
• Tian S, Hu W, Niu L, et al. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol. 2020;15(5):700–704.
   PubMed Web of Science ®Google Scholar
• Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020;77(2):198–209.
   PubMed Web of Science ®Google Scholar
• McGonagle D, O’Donnell JS, Sharif K, et al. Why the immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia are distinct from macrophage activation syndrome with disseminated intravascular coagulation. Lancet Rheum. 2020;2(7):437–445.
   PubMedGoogle Scholar
• Nishiga M, Wang DW, Han Y, et al. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol. 2020;17(9):543–558.
   PubMed Web of Science ®Google Scholar
• Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811–818.
   PubMed Web of Science ®Google Scholar
• Fox SE, Li G, Akmatbekov A, et al. Unexpected features of cardiac pathology in COVID-19 infection. circulation. 2020;142(11):1123–1125.
   PubMed Web of Science ®Google Scholar
• Basso C, Leone O, Rizzo S, et al. Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur heart J. 2020;41(39):3827–3835.
   PubMed Web of Science ®Google Scholar
• Knowlton KU. Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus. J Mol Cell Cardiol. 2020;147:12–17.
   PubMed Web of Science ®Google Scholar
• Gavriilaki E, Anyfanti P, Gavriilaki M, et al. Endothelial dysfunction in COVID-19: lessons learned from coronaviruses. Hypertens Heart. 2020;22. DOI:https://doi.org/10.1007/s11906-020-01078-6.
   Google Scholar
• Hanley B, Naresh KN, Roufosse C, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study. Lancet. 2020;1:245–253.
   Web of Science ®Google Scholar
• Vasquez-Bonilla WO, Orozco R, Argueta V, et al. A review of the main histopathological findings in coronavirus disease 2019. Hum Pathol. 2020;105:74–83.
   PubMed Web of Science ®Google Scholar
• Nair R, Maseeh A. Vitamin D: the “sunshine” vitamin. J Pharmacol Pharmacother. 2012;3(2):118–126.
   PubMedGoogle Scholar
• Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science. 1980;210(4466):203–205.
   PubMed Web of Science ®Google Scholar
• Fleet JC. Rapid, membrane-initiated actions of 1,25dihydroxyvitamin D: what are they and what do they mean? J Nutr. 2004;134(12):3215–3218.
   PubMed Web of Science ®Google Scholar
• Carlberg C. The vitamin D3 receptor in the context of the nuclear receptor superfamily: the central role of the retinoid X receptor. Endocrine. 1996;4(2):91–105.
   PubMed Web of Science ®Google Scholar
• Yu VC, Delsert C, Andersen B, et al. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell. 1991;67(6):1251–1266.
   PubMed Web of Science ®Google Scholar
• Tecle T, Tripathi S, Hartshorn KL. Defensins and cathelicidins in lung immunity. Innate Immun. 2010;16(3):151–159.
   PubMed Web of Science ®Google Scholar
• Leaf DE, Croy HE, Abrahams SJ, et al. Cathelicidin antimicrobial protein, vitamin D, and risk of death in critically ill patients. Crit Care. 2015;19(1):80.
   PubMedGoogle Scholar
• Fabbri A, Infante M, Ricordi C. Vitamin D status: a key modulator of innate immunity and natural defense from acute viral respiratory infections. Eur Rev Med Pharmacol Sci. 2020;24(7):4048–4052.
   PubMed Web of Science ®Google Scholar
• Chen H, Lu R, Zhang YG, et al. Vitamin D receptor deletion leads to the destruction of tight and adherens junctions in lungs. Tissue Barriers. 2018;6(4):1–13.
   PubMed Web of Science ®Google Scholar
• Shi YY, Liu TJ, Fu JH, et al. 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):1186–1194.
   PubMed Web of Science ®Google Scholar
• Zheng SX, Yang JX, Hu X, et al. Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-β induced epithelial to mesenchymal transition. Biochem Pharmacol. 2020;177:113955.
   PubMed Web of Science ®Google Scholar
• Sadeghi K, Wessner B, Laggner U, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2020;36(2):361–370.
   Google Scholar
• Zhao Y, Yu B, Mao X, et al. Dietary vitamin D supplementation attenuates immune responses of pigs challenged with rotavirus potentially through the retinoic acid-inducible gene I signalling pathway. Br J Nutr. 2014;112(3):381–389.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Leung DYM, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012;188(5):2127–2135.
   PubMed Web of Science ®Google Scholar
• Telcian AG, Zdrenghea MT, Edwards MR, et al. Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro. Antiviral Res. 2017;137:93–101.
   PubMed Web of Science ®Google Scholar
• Gal-Tanamy M, Bachmetov L, Ravid A, et al. Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology. 2011;54(5):1570–1579.
   PubMed Web of Science ®Google Scholar
• Feng X, Wang Z, Howlett-Prieto Q, et al. Vitamin D enhances responses to interferon-β in MS. Neurol Neuroimmunol Neuroinflamm. 2019;6(6):e622.
   PubMed Web of Science ®Google Scholar
• Lange CM, Gouttenoire J, Duong FHT, et al. Vitamin D receptor and Jak–STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-α. J Immunol. 6037-44;192. DOI:https://doi.org/10.1080/15384047.2016.1235669.
   Google Scholar
• Hansdottir S, Monick MM, Lovan N, et al. Vitamin D decreases respiratory syncytial virus induction of NF-κB–linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010;184(2):965–974.
   PubMed Web of Science ®Google Scholar
• Lemire JM, Adams JS, Kermani-Arab V, et al. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol. 1985;134(5):3032–3035.
   PubMed Web of Science ®Google Scholar
• Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest. 1991;87(3):1103–1107.
   PubMed Web of Science ®Google Scholar
• Cantorna MT. Mechanisms underlying the effect of vitamin D on the immune system. Proc Nutr Soc. 2010;69(3):286–289.
   PubMed Web of Science ®Google Scholar
• Wei R, Christakos S. Mechanisms underlying the regulation of innate and adaptive immunity by vitamin D. Nutrients. 2015;7(10):8251–8260.
   PubMed Web of Science ®Google Scholar
• Jeffrey LE, Burke F, Mura M, et al. 1,25-dihydroxyvitamin D3 and IL-2 combine to inhibit T Cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009;183(9):5458–5467.
   PubMed Web of Science ®Google Scholar
• Caprio M, Infante M, Calanchini M, et al. Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects. Eat Weight Disord. 2017;22(1):27–41.
   PubMed Web of Science ®Google Scholar
• Infante M, Ricordi C, Sanchez J, et al. Influence of Vitamin D on islet autoimmunity and beta-Cell function in Type 1 Diabetes. Nutrients. 2019;11(9):2185.
   PubMed Web of Science ®Google Scholar
• Xu J, Yang J, Chen J, et al. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system. Mol Med Repo. 2017;16(5):7432–7438.
   PubMed Web of Science ®Google Scholar
• Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2): 229–8.
   Web of Science ®Google Scholar
• Yang J, Xu J, Zhang H. Effect of vitamin D on ACE2 and vitamin D receptor expression in rats with LPS-induced acute lung injury. Chin J Emergency Med. 2016. DOI:https://doi.org/10.3760/CMA.J.1671-0282.2016.12.016
   Google Scholar
• Shi Y, Liu T, Yao L, et al. Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system. Sci Rep. 2017;7(1):3312.
   PubMedGoogle Scholar
• Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D (3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2):229–238.
   PubMed Web of Science ®Google Scholar
• Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab. 2005;288(1):125–132.
   Web of Science ®Google Scholar
• Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–116.
   PubMed Web of Science ®Google Scholar
• Dancer RCA, Parekh D, Lax S, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015;70(7):617–624.
   PubMed Web of Science ®Google Scholar
• Park S, Lee MG, Hong SB, et al. Effect of vitamin D deficiency in Korean patients with acute respiratory distress syndrome. Korean J Intern Med. 2019;34(3):685.
   PubMed Web of Science ®Google Scholar
• Remmelts HHF, Van De Garde EMW, Meijvis SCA. Peelen ELGCA et al. Addition of vitamin D status to prognostic scores improves the prediction of outcome in community-acquired pneumonia. Clin Infect Dis. 2012;55(11):1488–1494.
   PubMed Web of Science ®Google Scholar
• Barnett N, Zhao Z, Koyama T, et al. Vitamin D deficiency and risk of acute lung injury in severe sepsis and severe trauma: a case-control study. Ann Intensive Care. 2014;4(1):5.
   PubMedGoogle Scholar
• Mihos CG, De La Cruz J, Hernandez A, et al. Vitamin D deficiency and supplementation in cardiovascular disorders. Cardiol Rev. 2017;25(4):189–196.
   PubMed Web of Science ®Google Scholar
• McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease: a narrative review. Ann Intern Med. 2011;155(12):820–826.
   PubMed Web of Science ®Google Scholar
• Caprio M, Mammi C, Rosano GMC, et al. a novel player in endothelial function and dysfunction. Arch Med Sci. 2012;8:4–5.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Zhang M, Wang H, et al. Vitamin D supplementation improves endothelial dysfunction in patients with non-dialysis chronic kidney disease. Int Urol Nephrol. 2018;50(5):923–927.
   PubMed Web of Science ®Google Scholar
• Tangpricha V, Pearce EN, Chen TC, et al. Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002;112(8):659–662.
   PubMed Web of Science ®Google Scholar
• Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(87):1080S–60S.
   PubMedGoogle Scholar
• Vasarhelyi B, Satori A, Olajos F, et al. Low vitamin D levels among patients at Semmelweis University: retrospective analysis during a one-year period. Orv Hetil. 2011;152(32):1272–1277.
   PubMedGoogle Scholar
• D’Avolio A, Avataneo V, Manca A, et al. 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020;12(5):1359.
   PubMed Web of Science ®Google Scholar
• Baktash V, Hosack T, Patel N, et al. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Post Graduate Med J. 2020; postgradmedj-2020-138712. DOI:https://doi.org/10.1136/postgradmedj-2020-138712.
   Google Scholar
• Carpagnano GE, Lecce VD, Quaranta VN, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2020;1-7. DOI:https://doi.org/10.1007/s40618-020-01370-x.
   Google Scholar
• Karahan S, Katkat F. Impact of Serum 25(OH) Vitamin D level on mortality in patients with COVID-19 in Turkey. J Nutr Health Aging. 2020. DOI:https://doi.org/10.1007/s12603-020-1479-0
   Web of Science ®Google Scholar
• Jain A, Chaurasia R, Sengar NS, et al. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep. 2020;10(1):20191.
   PubMed Web of Science ®Google Scholar
• Meltzer DO, Best TJ, Zhang H, et al. Association of Vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Netw Open. 2020;3(9):e2019722.
   PubMed Web of Science ®Google Scholar
• Ilie PC, 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):1195–1198.
   PubMed Web of Science ®Google Scholar
• Rhodes JM, Subhramanian S, Laird E, et al. Editorial: low population mortality from COVID‐19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Aliment PharmacolTher. 2020;51(12):1434–1437.
   PubMed Web of Science ®Google Scholar
• Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(6):1678S–1688S.
   PubMed Web of Science ®Google Scholar
• Berridge MJ. Vitamin D deficiency and diabetes. Biochem J. 2017;474(8):1321–1332.
   PubMed Web of Science ®Google Scholar
• Nakashima A, Yokoyama K, Yokoo T, et al. Role of vitamin D in diabetes mellitus and chronic kidney disease. World J Diabetes. 2016;7(5):89–100.
   PubMed Web of Science ®Google Scholar
• Migliaccio S, Nisio AD, Mele C, et al. Obesity and hypovitaminosis D: causality or casualty? Int J Obes Suppl. 2019;9(1):20–31.
   PubMedGoogle Scholar
• Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? Lancet Diabetes Endocrinol. 2020;8(7):570.
   PubMed Web of Science ®Google Scholar
• Castillo ME, Costa LME, Barrios JMV, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020;203:105751.
   PubMed Web of Science ®Google Scholar
• Annweiler C, Hanotte B, de I’eprevier CG, et al. Vitamin D and survival in COVID-19 patients: a quasi-experimental study. J Steroid Biochem Mol Biol. 2020;204:105771.
   PubMed Web of Science ®Google Scholar
• Tan CW, Ho LP, Kalimuddin S, et al. Cohort study to evaluate the effect of vitamin D, magnesium, and vitamin B12 in combination on progression to severe outcomes in older patients with coronavirus (COVID-19). Nutrition. 2020;79-80:111017.
   PubMed Web of Science ®Google Scholar
• Annweiler G, Corvaisier M, Gautier J, et al. Vitamin D supplementation associated to better survival in hospitalized Frail Elderly COVID-19 Patients: the GERIA-COVID quasi-experimental study. Nutrients. 2020;12(11):3377.
   PubMed Web of Science ®Google Scholar
• Ling SF, Broad E, Murphy R, et al. High-Dose cholecalciferol booster therapy is associated with a reduced risk of mortality in patients with COVID-19: a cross-sectional multi-centre observational study. Nutrients. 2020;12(12):3799.
   Web of Science ®Google Scholar
• Ohaegbulam KC, Swalih M, Patel P, et al. Vitamin D supplementation in COVID-19 patients: a clinical case series. Am J Ther. 2020;27(5):485–490.
   PubMed Web of Science ®Google Scholar
• Giannini S, Passeri G, Tripepi G, et al. Effectiveness of in-hospital cholecalciferol use on clinical outcomes in comorbid COVID-19 patients: a hypothesis-generating study. Nutrients. 2021;13(1):219.
   PubMed Web of Science ®Google Scholar
• Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study). Postgrad Med J. 2020; postgradmedj-2020-139065. DOI:https://doi.org/10.1136/postgradmedj-2020-139065.
   PubMed Web of Science ®Google Scholar
• Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12(4):988.
   PubMed Web of Science ®Google Scholar
• Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – final report. N Engl J Med. 2020;383(19):1813–1826.
   PubMed Web of Science ®Google Scholar
• Cauchois R, Koubi M, Delarbre D, et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19. Proc Natl Acad Sci USA. 2020;117(32):18951–18953.
   PubMed Web of Science ®Google Scholar
• Cavalli G, Larcher A, Tomelleri A, et al. Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study. Lancet Rheumatol. 2021. DOI:https://doi.org/10.1016/s2665-9913(21)00012-6.
   Google Scholar
• Alijotas-Reig J, Esteve-Valverde E, Belizna C, et al. Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: a comprehensive review. Autoimmun Rev. 2020;19(7):102569.
   PubMed Web of Science ®Google Scholar
• Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2 - Mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020;11(2):216–228.
   PubMed Web of Science ®Google Scholar
• Mascolo S, Carleo MA, Contieri M, et al. SARS-CoV-2 and inflammatory responses: from mechanisms to the potential therapeutic use of intravenous immunoglobulin. J Med Virol. 2020. DOI:https://doi.org/10.1002/jmv.26651.
   Google Scholar
• Brown AJ, Slatoplosky E. Vitamin D analogs: therapeutic applications and mechanisms for selectivity. Mol Aspects Med. 2008;29(6):433–452.
   PubMed Web of Science ®Google Scholar
• Chen J, Tang Z, Slominski AT, et al. Vitamin D and its analogs as anticancer and anti-inflammatory agents. Eur J Med Chem. 2020;207:112738.
   PubMed Web of Science ®Google Scholar