The role of host lipids and exosomes in the pathogenesis of Johne’s disease

Paratuberculosis or Johne’s disease (JD) is a chronic granulomatous enteritis of ruminants such as cattle, sheep and goats. The causative agent, Mycobacterium avium subspecies paratuberculosis (MAP), is a slow-growing pathogenic mycobacterium, responsible for significant mortalities and economic losses within the global livestock sector. Upon exposure, MAP is transferred across the intestinal epithelium via M cells located within the Peyer’s patches, and into the intestinal submucosa where host macrophages detect and phagocytose MAP. However, MAP is able to establish an intracellular niche and remain in a dormant state within macrophages for an extended period prior to the re-emergence from host macrophages and the progression towards clinical disease. It is during this time that very little is known about the host-pathogen interactions responsible for intracellular persistence. The majority of our understanding of intracellular survival mechanisms in relation to mycobacterial disease stems from extensive research of M. tuberculosis pathogenesis. While there are many common survival strategies shared between MAP and M. tuberculosis, there are also unique pathogenic characteristics that may be responsible for their distinct host and tissue tropisms. As such, there is limited knowledge about the mechanisms MAP is able to utilise in host responses and pathways to aid in the establishment of infection and to create a favourable intracellular niche for extended survival. Furthermore, it is unknown whether MAP is able to utilise host pathways to communicate with neighbouring cells to trigger its re-emergence from host macrophages and facilitate the progression to clinical disease. This thesis focused on addressing these knowledge gaps by examining the role of host lipids in the establishment of infection and to investigate exosome generation and composition using both in vitro and in vivo experimental mycobacterial infection models