Abstract
Avian colibacillosis is the most frequently reported bacterial disease in poultry. Management of the causative agent, avian pathogenic Escherichia coli (APEC), is essential for maintaining animal health, welfare, and productivity within the poultry industry. However, the growing threat of antimicrobial resistance (AMR) has led to a demand for novel non-antibiotic disease management approaches. One such alternative is the enhancement of innate immune system responses by immunomodulation and immune training, demonstrated to provide broad-spectrum protection against bacterial pathogens in mammalian models. This thesis aimed to assess the utility of broad-spectrum innate immune modulation as a potential disease management strategy for APEC and identify candidate non-antibiotic immunomodulatory compounds. Initial investigations phenotypically characterised the genetically diverse APEC pathotype. High-risk clonal groups were observed to have heterogeneous interactions with avian host cells and distinct virulence capacities but elicited similar immunological responses, highlighting the potential pathotype-wide effect of innate immune modulation. The short chain fatty acid sodium butyrate, previously demonstrated to enhance murine macrophage antibacterial responses, was then investigated as a candidate immunomodulatory compound. Priming of both immortalised and bone marrow derived chicken macrophages with sodium butyrate reduced intramacrophage survival of multiple APEC genotypes, as well as other Gram-negative and Gram-positive pathogens. This was determined to be a result of inhibition of the mechanistic target of rapamycin (mTOR), increased production of reactive oxygen species (ROS), and enhanced autophagy. Sodium butyrate was also demonstrated to induce a trained immunity-like phenotype in chicken macrophages, altering responses to activation. Similarly to immune priming, this increased macrophage bactericidal activity against APEC clonal groups and other bacterial pathogens as a result of increased ROS production and autophagic activity. Collectively, the studies presented in this thesis highlight the potential of innate immune modulation as an effective approach to control bacterial diseases in poultry.