Peel, E. J. (2018). Peptides from the Pouch: Marsupial and Monotreme Cathelicidins. The University of Sydney.

The rise in antimicrobial resistance and paucity of new antimicrobial compounds calls for alternatives to traditional antibiotics. Antimicrobial peptides (AMPs) have emerged as potential candidates. Cathelicidins are a major family of AMPs in mammals which form part of innate immunity through antimicrobial and immunomodulatory functions. Marsupial and monotreme cathelicidins are of particular interest due to their involvement in protecting immunologically naive young during development in the pouch via expression in the pouch lining and milk where they modulate microbial flora and provide passive immunity. As such, the cathelicidin gene family has expanded in marsupials and monotremes, with a high number of cathelicidins in the tammar wallaby, gray short-tailed opossum and platypus. However our knowledge is limited to these species and functional studies involving antimicrobial activity are lacking. This thesis describes the characterisation of cathelicidins in the Tasmanian devil, koala and echidna, and investigates the antimicrobial function of all marsupial and monotreme cathelicidins. As expected, cathelicidins have expanded in the Tasmanian devil and koala, resulting in a high number of cathelicidins which were widely expressed throughout the body, including in pouch lining and milk. Only a single cathelicidin was identified in the echidna due to the quality of the genome. Out of 26 cathelicidins tested, six displayed broad-spectrum antibacterial activity against gram-negative and positive bacteria, including methicillin-resistant Staphylococcus aureus. One koala cathelicidin rapidly inactivated C. pecorum and significantly reduced the number of chlamydial inclusions in vitro. Activity was reduced in the presence of serum and whole blood, and peptides displayed varying levels of haemolytic and cytotoxic activity. Many cathelicidins did not display antimicrobial activity and future work is required to explore their potential immunomodulatory properties. The results presented in this thesis have advanced our understanding of cathelicidins in marsupials and monotremes on a genetic and functional level, and highlights their potential as novel therapeutics in the future.

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