Innate immunity in the oral epithelium represents the first line of defense against the pathogenic microorganisms that cause periodontal disease. As a result of an R21 grant, entitled "Vitamin D induction of antibacterial activity in gingival cells" e have recently shown that oral epithelial cells are capable of converting inactive vitamin D to the active form (1,25(OH)2 Vitamin D3), and that this hormone induces the expression of an antimicrobial peptide, LL-37, and other host defense mediators, resulting in an increase in the antibacterial innate immune defense against periopathogenic bacteria. Other studies have demonstrated a strong association between vitamin D levels and the host defense against infection in the oral cavity. Together the data provide strong support to our overarching hypothesis that vitamin D promotes innate immune defense in the gingival epithelium. To address this hypothesis, we propose a comprehensive analysis of the relationship, including both in vitro and in vivo experimental analyses to characterize the relationship between vitamin D and the innate immune defense in periodontal disease. We propose two aims: 1. Characterize the mechanism of vitamin D-mediated induction of innate immunity in gingival epithelial cells (GEC). We will better understand the induction by defining the response to 1,25(OH)2D3 with respect to transcriptional control of innate immune gene expression and the interaction with the innate immune response pathways. This will be the first characterization of the molecular pathways associated with vitamin D in oral epithelial cells, and of the cross-talk with innate immune pathways. Doing so will provide a greater understanding of innate immunity in the oral cavity. 2. Quantify the relationship between vitamin D and periodontal disease in a mouse model of bacteria-induced periodontal disease. We hypothesize that regulating serum vitamin D levels directly correlates with innate immune defense capability in the gingival epithelium. To confirm this in vivo, we will determine the effect of vitamin D depletion in a bacteria-based mouse model of periodontal disease. Since the mouse homologue to LL-37 is not induced by vitamin D, we will also use a humanized strain that expresses LL-37 under the control of its own (human, vitamin D-regulated) promoter. We will also supplement both local and systemic vitamin D levels to quantify the effect of increased concentrations on the innate immune defenses. While long examined for its role in human health, the results we expect to obtain from this study would represent the first mechanistic analysis of the contribution of vitamin D to defense against a chronic infectious disease such as periodontitis, and will provide the basis for the development of vitamin D as a therapeutic agent.
Periodontal disease is caused by bacteria that adhere to and colonize the gingival cells adjacent to the teeth. Our published results from a funded R21 demonstrated that vitamin D can increase the immune defenses of gingival cells against the bacteria associated with periodontal disease. Here we propose to study the mechanism by which this occurs, and to determine whether we can prevent bacteria-induced periodontal disease in a mouse model. The results will support the development of vitamin D as a therapy for periodontal disease and other oral infections.