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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

Chen et al., MedComm, doi:10.1002/mco2.318

Jun 2023

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Vitamin D for COVID-19

8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.

Lower risk for mortality, ICU, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 112 treatments. c19early.org

In Vitro and mouse study showing that vitamin D3 attenuates SARS-CoV-2 nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway. In human bronchial epithelial cells overexpressing the N protein, vitamin D3 dose-dependently reduced IL-6 and IL-1β expression and secretion. Authors find that vitamin D3 inhibited N protein-triggered NLRP3 inflammasome activation, an effect enhanced by NLRP3 and caspase-1 inhibitors or siRNAs. Vitamin D3 increased NLRP3 ubiquitination and VDR-NLRP3 binding while decreasing BRCC3-NLRP3 association. In N protein-expressing mice, vitamin D3 improved lung injury and decreased NLRP3 inflammasome activation and hyperinflammation in a VDR-dependent manner.

23 preclinical studies support the efficacy of vitamin D for COVID-19:

8 In Silico studies1-8

12 In Vitro studies9-20

3 In Vivo animal studies12,16,21

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 function22-25. Vitamin D inhibits SARS-CoV-2 replication in vitro12,19, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections12,19, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression15, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells11, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway16, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects26, downregulates ACE2 and TMPRSS2 in human trophoblasts and minimizes spike protein-induced inflammation14, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling10, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1927. Calcifediol inhibits SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication9. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity28,29.

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1. Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.springer.com, doi.org.

2. 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.f1000research.com, doi.org.

3. 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.sciencedirect.com, doi.org.

4. 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.sciencedirect.com, doi.org.

5. 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.nature.com, doi.org.

6. 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.tandfonline.com, doi.org.

7. 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.physiology.org, doi.org.

8. 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.journaljpri.com, doi.org.

9. 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.wiley.com, doi.org.

10. 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.wiley.com, doi.org.

11. 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.mdpi.com, doi.org.

12. Campolina-Silva et al., Dietary Vitamin D Mitigates Coronavirus-Induced Lung Inflammation and Damage in Mice, Viruses, doi:10.3390/v15122434.mdpi.com, doi.org.

13. 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.mdpi.com, doi.org.

14. 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.sciencedirect.com, doi.org.

15. 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.nih.gov, doi.org.

16. 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.wiley.com, doi.org.

17. 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.wiley.com, doi.org.

18. 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.tandfonline.com, doi.org.

19. 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.plos.org, doi.org.

20. 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.biorxiv.org, doi.org.

21. 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.mdpi.com, doi.org.

22. 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.mdpi.com, doi.org.

23. 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.mdpi.com, doi.org.

24. 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.europa.eu, doi.org.

25. 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.wiley.com, doi.org.

26. 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.karger.com, doi.org.

27. 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.nature.com, doi.org.

28. Graydon et al., High baseline frequencies of natural killer cells are associated with asymptomatic SARS-CoV-2 infection, Current Research in Immunology, doi:10.1016/j.crimmu.2023.100064.sciencedirect.com, doi.org.

29. Oh et al., Vitamin D and Exercise Are Major Determinants of Natural Killer Cell Activity, Which Is Age- and Gender-Specific, Frontiers in Immunology, doi:10.3389/fimmu.2021.594356.frontiersin.org, doi.org.

Chen et al., 21 Jun 2023, peer-reviewed, 11 authors. Contact: hongbinsong@263.net, bianxiuwu@263.net.

This Paper Vitamin D All

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

Mingliang Chen, Ying He, Xiaofeng Hu, Xunhu Dong, Zexuan Yan, Qingning Zhao, Jingyuan Li, Dongfang Xiang, Yong Lin, Ph.D Hongbin Song, M.D Xiuwu Bian

MedComm, doi:10.1002/mco2.318

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-caused coronavirus disease 2019 (COVID-19) is a global crisis with no satisfactory therapies. Vitamin D3 (VD3) is considered a potential candidate for COVID-19 treatment; however, little information is available regarding the exact effects of VD3 on SARS-CoV-2 infection and the underlying mechanism. Herein, we confirmed that VD3 reduced SARS-CoV-2 nucleocapsid (N) protein-caused hyperinflammation in human bronchial epithelial (HBE) cells. Meanwhile, VD3 inhibited the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in N protein-overexpressed HBE (HBE-N) cells. Notably, the inhibitors of caspase-1, NLRP3, and NLRP3 or caspase-1 small interference RNA (siRNA) enhanced VD3-induced NLRP3 inflammasome inactivation, with subsequent suppression of interleukin-6 (IL6) and IL1β release in HBE-N cells, which were abolished by the NLRP3 agonist. Moreover, VD3 increased NLRP3 ubiquitination (Ub-NLRP3) expression and the binding of the VDR with NLRP3, with decreased BRCA1/BRCA2-containing complex subunit 3 (BRCC3) expression and NLRP3-BRCC3 association. VD3-induced Ub-NLRP3 expression, NLRP3 inflammasome inactivation, and hyperinflammation inhibition were improved by the BRCC3

AUTHOR CONTRIBUTIONS A C K N O W L E D G M E N T S We are particularly grateful to Figdraw (https://www. figdraw.com/static/index.html) for providing a useful tool to draw the diagram of the mechanism. This work was supported by the National Natural Science Foundation of China (grant numbers: 82073544 and 82202189) and the Beijing Municipal Natural Science Foundation of China (grant number: 7232229). C O N F L I C T O F I N T E R E S T S TAT E M E N T The authors declare no conflict of interest. D ATA AVA I L A B I L I T Y S TAT E M E N T All data and materials are available to the researchers once published. E T H I C S S TAT E M E N T All animal experiments were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health and were approved by the Animal Care and Use Committee of the Army Medical University (AMUWEC20212432, Chongqing, China). O R C I D Xiaofeng Hu https://orcid.org/0000-0003-0569-8535 R E F E R E N C E S S U P P O R T I N G I N F O R M AT I O N Additional supporting information can be found online in the Supporting Information section at the end of this article.

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