Analyses of murine beta defensins and defensin inspired peptides

Abstract

Antimicrobial peptides are important components of the innate immune systems ability to fight disease. They display widespread distribution throughout the animal and plant kingdom and directly inhibit infection rapidly. In numerous cases these peptides provide additional roles acting upon the immune system to co-ordinate a protective response. The defensins, one of the largest antimicrobial peptide families, can be subclassed into the α, ß and θ defensins based on their six cysteine spacing and connectivity. The (ß- defensins which are expressed at a variety of epithelial surfaces, display antimicrobial properties and play important roles in host defence.The aim of this project was 1) to evaluate the antimicrobial and chemoattractant properties of a novel five cysteine defensin related peptide (Defrl), 2) to analyse Defbl4, the murine orthologue of human beta defensin 3 and 3) to investigate the properties of defensin inspired peptides.This thesis describes the antimicrobial and chemoattractant properties of Defrl. This work suggests that Defrl displayed antimicrobial activity against a panel of organisms for which antimicrobial treatment is limited or non-existent. In addition Defrl displayed potent chemoattractant properties regarding various immune cell types and is the first example of a ß-defensin that does not act through CCR6Data presented in this thesis describes the first study of the murine peptide Defbl4. This concluded that a synthetic preparation of Defbl4 displayed potent antimicrobial activity and roles within immune cell migration.In this thesis, various defensin inspired peptides were subjected to study. Defbl4 was used as a template for functional analysis and concluded that smaller N-terminal peptides displayed potent antimicrobial activity. Interestingly chemotactic activity was absent and toxicity remained similar to that of the original Defbl4. These studies have highlighted the role of defensin inspired peptides as potential therapeutic agents.