The emergence of antibiotic-resistant microorganisms has heightened interest in the study of endogenous antimicrobial substances and their role in host defense. Recently, numerous antimicrobial peptides have been isolated from mammals, amphibians and insects representing a broad and previously unrecognized component of animal host defense. Tracheal Antimicrobial peptide (TAP), made by bovine airway epithelial cells, is one such peptide that was discovered by our group. The long range goal of this research initiative is to better understand innate host defense mechanisms with a principal focus on defining the role of antimicrobial peptides of epithelial origin. Our results in this area during the preceding funding period have led us to formulate a hypothesis: Induction of TAP (or TAP-like) gene expression by bacterial and inflammatory stimuli constitutes part of an active host defense response of challenged tracheal epithelial cells (TEC). Preliminary studies showing significant elevations of TAP mRNA in airway epithelial cells exposed to either bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) yield evidence in support of this model. The following experiments are proposed in order to test this hypothesis further, and to develop necessary human- and mouse-specific reagents to extend these lines of investigation: 1) Characterize the induction of TAP expression at the peptide and gene levels in challenged TEC; 2) Determine the mechanism by which inflammatory mediators trigger the innate host defense response of TEC; 3) Characterize the recently identified family of human TAP (beta-defensin) homologues; and 4) Develop a small animal model to study beta-defensin regulation and function. Epithelial TAP-like peptides are likely to equip mucosal surfaces with a previously unrecognized defensive capability that complements other well-defined antimicrobial defenses. Defining the mechanisms regulating expression of these antimicrobial peptides will enhance our understanding of basic host defense mechanisms and may lead to the development of useful therapeutics.
