Antimicrobial peptides (APs) are innate immune system components that are anti-bacterial, anti-viral, and anti-fungal and, as such, show great promise as therapeutic and/ or prophylactic antimicrobials for the treatment of otitis media (OM), an illness which can lead to signficant heaing loss and language development delays in children. A significant roadblock to our long-term goal of developing novel treatments for OM is the incomplete understanding of APs which are operative in the upper airway. To this end, we have begun characterization of APs in the upper respiratory tract (URT) of the chinchilla, the predominant host used to model experimental otitis media. Recently, we identified a novel AP, csPLUNC-1, which is specifically expressed in the URT of the chinchilla and is bactericidal. We show that the human homolog of this AP can kill bacterial causative agents of OM, and is produced in the pediatric middle ear supporting our assertion that understanding chinchilla sPLUNC-1 has relevance to innate immunity in humans. Here, we propose experiments in which we aim to determine the mRNA and protein expression profile for csPLUNC-1 by epithelial cells of the chinchilla upper airway after exposure to bacterial causative agents of OM, determine the breadth of the antimicrobial activity of csPLUNC-1, as well as map the functional domains of this peptide employing a genetic mutagenesis approach. Lastly, we will determine whether glycosylation of csPLUNC influences the IPS binding, microbial killing and/or half-life characteristics of this peptide. Data generated from these studies will likely not only provide a foundation for understanding this new class of APs, but will also contribute to a greater understanding of how the host protects its mucosal surfaces and how microbes respond to these effectors of innate immunity. The experiments proposed in this application will enable the candidate to gain further experience in animal modeling of disease and characterizing APs, in a research environment which is rich in resources and mentorship. This training, coupled with the unique research area provides an excellent opportunity for a future in academia. Antimicrobial peptides posssess great potential for use in treating infectious disease. The research in this application describes the characterization of a new antimicrobial peptide and presents approaches to further understand this protein. ? ? ?
| McGillivary, Glen; Bakaletz, Lauren O (2010) The multifunctional host defense peptide SPLUNC1 is critical for homeostasis of the mammalian upper airway. PLoS One 5:e13224 |
