1,25‐Dihydroxyvitamin D3 attenuates platelet aggregation potentiated by SARS‐CoV‐2 spike protein via inhibiting integrin αIIbβ3 outside‐in signaling
et al., Cell Biochemistry and Function, doi:10.1002/cbf.4039, May 2024
Vitamin D for COVID-19
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In vitro study showing that calcitriol minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling. Authors find that calcitriol reduces platelet aggregation and Src-mediated signaling induced by the spike protein. Specifically, calcitriol attenuated spike protein-enhanced platelet spreading and the phosphorylation of β3, c-Src, and Syk. Using the Src family kinase inhibitor PP2, authors confirmed that the combination with calcitriol did not show additive inhibitory effects, suggesting that calcitriol operates through the same pathway.
29 preclinical studies support the efficacy of vitamin D for COVID-19:
Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function27-30.
Vitamin D inhibits SARS-CoV-2 replication in vitro17,24, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections17,24, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression20, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells16, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway21, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects31, may mitigate hyperinflammation and cytokine storm by upregulating TLR10 expression which downregulates proinflammatory cytokines13, downregulates ACE2 and TMPRSS2 in human trophoblasts and minimizes spike protein-induced inflammation19, may minimize cytokine storm by dampening excessive cytokine production2, may suppress viral entry and replication via LL-37 induction11,12, and minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling15.
Cholecalciferol and calcifediol directly bind two allosteric pockets on the SARS-CoV-2 Spike RBD, bias the trimer toward a closed state, weaken ACE2 engagement, and reduce viral entry in cell models1.
Vitamin D improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1932.
Calcifediol inhibits SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication14.
Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity33,34.
1.
García-Marín et al., Exploring SARS-CoV-2 Spike RBD Pockets as Targets for Generic Drugs: A Combined Computational, Biophysical, and Biological Approach, ACS Omega, doi:10.1021/acsomega.5c05175.
2.
Alzahrani, A., A new investigation into the molecular mechanism of cholecalciferol towards reducing cytokines storm, Octahedron Drug Research, doi:10.21608/odr.2024.308273.1043.
3.
Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.
4.
Morales-Bayuelo et al., New findings on ligand series used as SARS-CoV-2 virus inhibitors within the frameworks of molecular docking, molecular quantum similarity and chemical reactivity indices, F1000Research, doi:10.12688/f1000research.123550.3.
5.
Chellasamy et al., Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors, Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277.
6.
Pandya et al., Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951.
7.
Mansouri et al., The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach, Scientific Reports, doi:10.1038/s41598-022-04778-y.
8.
Song et al., Vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19: a computational study, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1964601.
9.
Qayyum et al., Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes, Endocrinology and Metabolism, doi:10.1152/ajpendo.00174.2021.
10.
Al-Mazaideh et al., Vitamin D is a New Promising Inhibitor to the Main Protease (Mpro) of COVID-19 by Molecular Docking, Journal of Pharmaceutical Research International, doi:10.9734/jpri/2021/v33i29B31603.
11.
Roth et al., Vitamin D-inducible antimicrobial peptide LL-37 binds SARS-CoV-2 Spike and accessory proteins ORF7a and ORF8, Frontiers in Cellular and Infection Microbiology, doi:10.3389/fcimb.2025.1671738.
12.
Vercellino et al., Influence of Sex and 1,25α Dihydroxyvitamin D3 on SARS-CoV-2 Infection and Viral Entry, Pathogens, doi:10.3390/pathogens14080765.
13.
Knez et al., TLR10 overexpression modulates immune response in A549 lung epithelial cells challenged with SARS-CoV-2 S and N proteins, Frontiers in Immunology, doi:10.3389/fimmu.2024.1490478.
14.
Chen et al., In Vitro Characterization of Inhibition Function of Calcifediol to the Protease Activity of SARS-COV-2 PLpro, Journal of Medical Virology, doi:10.1002/jmv.70085.
15.
Wang et al., 1,25‐Dihydroxyvitamin D3 attenuates platelet aggregation potentiated by SARS‐CoV‐2 spike protein via inhibiting integrin αIIbβ3 outside‐in signaling, Cell Biochemistry and Function, doi:10.1002/cbf.4039.
16.
Alcalá-Santiago et al., Disentangling the Immunomodulatory Effects of Vitamin D on the SARS-CoV-2 Virus by In Vitro Approaches, The 14th European Nutrition Conference FENS 2023, doi:10.3390/proceedings2023091415.
17.
Campolina-Silva et al., Dietary Vitamin D Mitigates Coronavirus-Induced Lung Inflammation and Damage in Mice, Viruses, doi:10.3390/v15122434.
18.
Moatasim et al., Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E, Microorganisms, doi:10.3390/microorganisms11112777.
19.
Vargas-Castro et al., Calcitriol prevents SARS-CoV spike-induced inflammation in human trophoblasts through downregulating ACE2 and TMPRSS2 expression, The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2024.106625.
20.
Sposito et al., Age differential CD13 and interferon expression in airway epithelia affect SARS-CoV-2 infection - effects of vitamin D, Mucosal Immunology, doi:10.1016/j.mucimm.2023.08.002.
21.
Chen (B) et al., Vitamin D3 attenuates SARS‐CoV‐2 nucleocapsid protein‐caused hyperinflammation by inactivating the NLRP3 inflammasome through the VDR‐BRCC3 signaling pathway in vitro and in vivo, MedComm, doi:10.1002/mco2.318.
22.
Rybakovsky et al., Calcitriol modifies tight junctions, improves barrier function, and reduces TNF‐α‐induced barrier leak in the human lung‐derived epithelial cell culture model, 16HBE 14o‐, Physiological Reports, doi:10.14814/phy2.15592.
23.
DiGuilio et al., The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function, Experimental Lung Research, doi:10.1080/01902148.2023.2193637.
24.
Pickard et al., Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells, PLOS Pathogens, doi:10.1371/journal.ppat.1009840.
25.
Mok et al., Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis, bioRxiv, doi:10.1101/2020.06.21.162396.
26.
Fernandes de Souza et al., Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D, Cells, doi:10.3390/cells12071092.
27.
Galmés et al., Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations, Nutrients, doi:10.3390/nu14112254.
28.
Galmés (B) et al., Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, Nutrients, doi:10.3390/nu12092738.
29.
EFSA, Scientific Opinion on the substantiation of a health claim related to vitamin D and contribution to the normal function of the immune system pursuant to Article 14 of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2015.4096.
30.
EFSA (B), Scientific Opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (E, EFSA Journal, doi:10.2903/j.efsa.2010.1468.
31.
Gotelli et al., Understanding the immune-endocrine effects of vitamin D in SARS-CoV-2 infection: a role in protecting against neurodamage?, Neuroimmunomodulation, doi:10.1159/000533286.
32.
Saheb Sharif-Askari et al., Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons, Scientific Reports, doi:10.1038/s41598-023-43675-w.
Wang et al., 15 May 2024, peer-reviewed, 6 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
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"abstract": "<jats:title>Abstract</jats:title><jats:p>Platelet hyperreactivity contributes to the pathogenesis of COVID‐19, which is associated with a hypercoagulability state and thrombosis disorder. It has been demonstrated that Vitamin D deficiency is associated with the severity of COVID‐19 infection. Vitamin D supplement is widely used as a dietary supplement due to its safety and health benefits. In this study, we investigated the direct effects and underlying mechanisms of 1,25(OH)<jats:sub>2</jats:sub>D<jats:sub>3</jats:sub> on platelet hyperreactivity induced by SRAS‐CoV‐2 spike protein via Western blot and platelet functional studies in vitro. Firstly, we found that 1,25(OH)<jats:sub>2</jats:sub>D<jats:sub>3</jats:sub> attenuated platelet aggregation and Src‐mediated signaling. We further observed that 1,25(OH)<jats:sub>2</jats:sub>D<jats:sub>3</jats:sub> attenuated spike protein‐potentiated platelet aggregation in vitro. Mechanistically, 1,25(OH)<jats:sub>2</jats:sub>D<jats:sub>3</jats:sub> attenuated spike protein upregulated‐integrin αIIbβ3 outside‐in signaling such as platelet spreading and the phosphorylation of β3, c‐Src and Syk. Moreover, using PP2, the Src family kinase inhibitor to abolish spike protein‐stimulated platelet aggregation and integrin αIIbβ3 outside‐in signaling, the combination of PP2 and 1,25(OH)<jats:sub>2</jats:sub>D<jats:sub>3</jats:sub> did not show additive inhibitory effects on spike protein‐potentiated platelet aggregation and the phosphorylation of β3, c‐Src and Syk. Thus, our data suggest that 1,25(OH)<jats:sub>2</jats:sub>D<jats:sub>3</jats:sub> attenuates platelet aggregation potentiated by spike protein via downregulating integrin αIIbβ3 outside‐in signaling.</jats:p>",
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