A Novel Immunomodulatory Mechanism by Which Vitamin D Influences Folate Receptor 3 Expression to Reduce COVID-19 Severity.

Background/aim: Identify potential mechanisms involving gene expression changes through which vitamin D supplementation could be beneficial in preventing adverse COVID-19 outcomes.

Materials And Methods: We performed a literature review to identify differentially expressed genes (DEGs) in the blood between severe and mild COVID-19 patients. We compared these with the top DEGs induced by 6 months of 10,000 IU/day vitamin D supplementation in healthy adults who were vitamin D deficient/insufficient. We used bioinformatic tools to look for a vitamin D response element (VDRE) in DEGs.

Results: FOLR3, RGS1, GPR84, and LRRN3 were the most significantly altered genes by 6 months of 10,000 IU/day vitamin D supplementation whose expression levels were also involved in COVID-19 severity. FOLR3 and GPR84 were found to be consistently up-regulated and RGS1 and LRRN3 consistently down-regulated in severe COVID-19 infection. FOLR3 and LRRN3 were down-regulated and RGS1 and GPR84 were up-regulated by 10,000 IU/day vitamin D supplementation.

Conclusion: FOLR3 and RGS1 are expressed in neutrophils and lymphocytes, respectively. Vitamin D supplementation may decrease the neutrophil-lymphocyte ratio as has been reported in patients admitted with severe symptoms. There is evidence that vitamin D directly influences the expression of the RGS1 gene through vitamin D receptor binding. A potential negative VDRE (nVDRE) in an intron of the FOLR3 gene was found, which was homologous with two known nVDREs. Combined with other transcription factor elements near the newly identified nVDRE, these observations may explain the mechanism by which vitamin D regulates these genes, thus influencing COVID-19 outcomes.