Vitamin D Linked to Shifts in Non-Coding RNA Networks During Zika Virus Infection in Human Macrophages

A new exploratory transcriptomic study suggests that vitamin D conditioning is associated with broad shifts in non-coding RNA expression and predicted regulatory networks in human macrophages infected with Zika virus, highlighting candidate lncRNA–miRNA–mRNA axes for future experimental validation.

Published in Pathophysiology, the analysis examined RNA-seq and miRNA-seq data from monocyte-derived macrophages (MDMs) obtained from four healthy donors and differentiated with or without 1 nM 1,25-dihydroxyvitamin D3 prior to infection with a Zika virus strain at MOI 5, with harvesting at 24 hours post-infection. The investigators focused on differential expression and integrative network modeling to evaluate how vitamin D exposure might be linked to post-transcriptional regulation during infection.

In the vitamin D–conditioned, Zika-infected comparison (ZIKV-D3-MDM vs ZIKV-MDM), the authors report significant modulation of 65 lncRNAs (defined as |fold change| ≥ 2 and FDR ≤ 0.05) and 23 miRNAs (FDR ≤ 0.05 and |fold change| ≥ 1.5). Several highlighted transcripts—including lncRNAs such as HSD11B1-AS1, Lnc-FOSL2, SPIRE-AS1, PCAT7, SOX2-OT, and SLC9A3-AS1, and miRNAs including let-7a, miR-494, miR-146a, miR-708, and miR-378—were discussed as candidates with prior links in the literature to immune regulation, metabolism, or inflammatory signaling.

To contextualize these changes, the study used functional enrichment approaches (e.g., EnrichR KEGG/GO) and integrated predicted miRNA targets with differentially expressed mRNAs, emphasizing pathways related to metabolism, cellular stress responses, and cell migration. The authors then constructed putative competing endogenous RNA (ceRNA) networks by combining differential expression patterns with curated interaction resources, filtering for inverse relationships between miRNAs and lncRNAs and incorporating lncRNA–mRNA interactions. These models suggested that certain lncRNAs (notably SOX2-OT and SLC9A3-AS1) could participate in regulatory axes consistent with miRNA “sponging,” although these interactions remain computationally inferred.

The paper also explored potential vitamin D receptor (VDR) involvement by examining VDR ChIP-seq data (in a macrophage model system) for proximity of VDR binding to loci associated with selected differentially expressed genes and miRNAs, supporting the possibility that some observed transcriptional changes are VDR-linked.

The authors underscore key limitations: the modest donor sample size and the lack of functional experiments to confirm predicted ncRNA interactions or establish causality for downstream biological effects. As presented, the findings are best interpreted as hypothesis-generating, offering a candidate map of vitamin D–associated ncRNA–mRNA networks during Zika infection in macrophages and prioritizing molecules and pathways for follow-up mechanistic studies.