Ontogeny Of Oral Epithelial Antimicrobial Peptides

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DESCRIPTION (provided by applicant): The innate immune system, an evolutionarily ancient response, is believed to be present and functional at birth or within the first few days of life. However, the role commensal bacteria play in "turning on" innate immunity; i.e., regulating it's response, and at what ontogenic point in life this begins to occur is not known. Recent findings in our laboratory are leading us to conjecture that ontogeny of the oral innate immune response may be linked to colonizing organisms in the oral cavity. We recently discovered that Fusobacterium nucleatum, a ubiquitous Gram-negative bacterium of the human oral cavity, induces expression of epithelial cell derived human beta defensin -2 (hBD-2) and hBD-3 in normal oral epithelial cells (NHOECs), resulting in protection against invasion of Porphyromonas gingivalis, a major etiologic agent in periodontal destruction. Extensive biochemical and molecular biological work has identified an F. nucleatum outer membrane protein that induces these antimicrobial and immunoregulatory peptides. We refer to this protein as FAD-I for Fusobacterial associated defensin inducer. Additionally, preliminary cross-sectional data indicates that salivary hBD levels are significantly lower in infancy than in older age groups. We suspect that an age-related association with hBD induction, and possibly other epithelial cell derived antimicrobial peptides (AMPs), is correlated with colonization and persistence of FAD-I expressing F. nucleatum strains. Clearly we need to know more about this dynamic by (1) conducting epidemiologic studies to investigate AMP levels across the age spectrum to establish overall, age stratified and FAD-I associated distributions; (2) determining the inductive properties of FAD-I on AMPs and their subsequent contribution to NHOEC protection and (3) further characterizing the functionality of FAD-I by taking molecular and biochemical approaches to ascertain preliminary structure-function relationships in hBD induction. By better understanding the ontogenic spectrum of an individual's innate immune AMP profile, we may be able to identify individuals who are predisposed to mucosal infections. By uncovering potential beneficial commensal strategies with the host, as FAD-I appears to be, we may one day be able to exploit these strategies in protecting susceptible mucosal sites. FAD-I is a new discovery that warrants investigation into the possibility that it or its derivatives may provide a new direction into drug design that could be exploited locally to bolster Mother Nature's own defenses.