Abstract
Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes β-defensin 2/defensin-β4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.
Highlights
This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which cathelicidin antimicrobial peptide (CAMP) and HBD2/DEFB4 contribute to antiviral immunity
Cathelicidin antimicrobial peptide (CAMP) is stimulated by the vitamin D receptor (VDR) bound to promoter-proximal vitamin D response elements
Calcitriol binds to the nuclear vitamin D receptor (VDR), a ligand regulated transcription factor [6], and exerts its physiological actions by directly or indirectly regulating gene expression
Summary
Vitamin D was discovered as the cure for nutritional rickets, which arises from insufficient uptake of dietary calcium. Over the years, evidence accumulated that the physiological actions of vitamin D signaling were not limited to control of calcium status Study of these “non-classical actions” of vitamin D was spurred on by the observations that the VDR and CYP27B1 were expressed in several tissues not implicated in calcium homeostasis [7]. Perhaps the best-established non-classical role of vitamin D3 is in the immune system Both the VDR and CYP27B1 are expressed in cells of the innate and adaptive arms of the immune system, and, critically, expression of CYP27B1 in immune cells in humans is regulated by pathogen detection and a complex cytokine network [8–11], independently of calcium homeostasis. Human beta-defensin 2 (HBD2/DEFB4) genes contain consensus vitamin D response elements (VDREs), binding sites for the VDR [19] These results reveal that calcitriol signaling induces the expression of numerous components of a robust innate immune response. These are described in the text as preprints or material yet to be subjected to peer review and their contents should be treated with caution
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