The study shows that the virus that causes cytomegalovirus can quickly shut down the body’s vitamin‑D receptor, making vitamin‑D supplements less effective against it. This shutdown is driven by a protein called Snail1, and drugs that affect gene‑silencing can partly reverse it. Importantly, adding the vitamin‑D‑triggered antimicrobial peptide LL‑37 directly to infected cells dramatically cut the amount of virus, suggesting that LL‑37 (or similar peptides) might be a useful antiviral tool when vitamin‑D pathways are blocked.

Vitamin-D supplementation is considered to play a beneficial role against multiple viruses due to its immune-regulating and direct antimicrobial effects. In contrast, the human cytomegalovirus (HCMV) has shown to be resistant to treatment with vitamin D in vitro by downregulation of the vitamin-D receptor. In this study, we aimed to elucidate the mechanism and possible biological consequences of vitamin-D resistance during HCMV infection. Mechanistically, HCMV induced vitamin-D resistance by downregulating the vitamin-D receptor (VDR) within hours of lytic infection. We found that the VDR was inhibited at the promoter level, and treatment with histone deacetylase inhibitors could restore VDR expression. VDR downregulation highly correlated with the upregulation of the transcriptional repressor Snail1, a mechanism likely contributing to the epigenetic inactivation of the VDR promoter, since siRNA-mediated knockdown of Snail partly restored levels of VDR expression. Finally, we found that direct addition of the vitamin-D-inducible antimicrobial peptide LL-37 strongly and significantly reduced viral titers in infected fibroblasts, highlighting VDR biological relevance and the potential of vitamin-D-inducible peptides for the antiviral treatment of vitamin-D deficient patients.