Antimicrobial peptide D1

Vitamin D, best known for its role in skeletal health, has emerged as a key regulator of innate immune responses to microbial threat. In immune cells such as macrophages, expression of CYP27B1, the 25-hydroxyvitamin D 1α-hydroxylase, is induced by immune-specific inputs, leading to local production of hormonal 1,25-dihydroxyvitamin D (1,25D) at sites of infection, which in turn directly induces the expression of genes encoding antimicrobial peptides. Vitamin D signaling is active upstream and downstream of pattern recognition receptors, which promote front-line innate immune responses. Moreover, 1,25D stimulates autophagy, which has emerged as a mechanism critical for control of intracellular pathogens such as M. tuberculosis. Strong laboratory and epidemiological evidence links vitamin D deficiency to increased rates of conditions such as dental caries, as well as inflammatory bowel diseases arising from dysregulation of innate immune handling intestinal flora. 1,25D is also active in signaling cascades that promote antiviral innate immunity; 1,25D-induced expression of the antimicrobial peptide CAMP/LL37, originally characterized for its antibacterial properties, is a key component of antiviral responses. Poor vitamin D status is associated with greater susceptibility to viral infections, including those of the respiratory tract. Although the severity of the COVID-19 pandemic has been alleviated in some areas by the arrival of vaccines, it remains important to identify therapeutic interventions that reduce disease severity and mortality, and accelerate recovery. This review outlines of our current knowledge of the mechanisms of action of vitamin D signaling in the innate immune system. It also provides an assessment of the therapeutic potential of vitamin D supplementation in infectious diseases, including an up-to-date analysis of the putative benefits of vitamin D supplementation in the ongoing COVID-19 crisis.

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.

The antimicrobial peptide database (APD, http://aps.unmc.edu/AP/) is an original database initially online in 2003. The APD2 (2009 version) has been regularly updated and further expanded into the APD3. This database currently focuses on natural antimicrobial peptides (AMPs) with defined sequence and activity. It includes a total of 2619 AMPs with 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides. The APD3 contains 2169 antibacterial, 172 antiviral, 105 anti-HIV, 959 antifungal, 80 antiparasitic and 185 anticancer peptides. Newly annotated are AMPs with antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties. We also describe other searchable annotations, including target pathogens, molecule-binding partners, post-translational modifications and animal models. Amino acid profiles or signatures of natural AMPs are important for peptide classification, prediction and design. Finally, we summarize various database applications in research and education.