Characterising the Role of Host-Pathogen Interactions in Systemic Bacterial Infections

Systemic bacterial infection Is defined as an infection of the of the bloodstream and if left untreated, can progress into sepsis and/or meningitis, causing significant morbidity and mortality worldwide. However, despite extensive research on the pathology of the disease, the precise mechanisms and host/bacterial determinants are still widely unknown. Therefore, development of an appropriate model would be highly beneficial in the study of host-pathogen interactions. The focus of this thesis was to development of a model and study the pathogenesis of S. pneumoniae, H. influenzae and N. meningitidis leading to the progression of sepsis and meningitis. Although, modelling infection with H. influenzae and N. meningitidis was unsuccessful, immunohistochemistry of meningococcal infected brain samples alluded potential involvement of CD169 macrophages in disease. It was previously reported that CD169 macrophages acted as an immune sanctuary for S. pneumoniae. Therefore, I explored the involvement of cell death pathways and pneumococcus during systemic infection. Although no statistical difference was observed, mice treated with a pyroptosis inhibitor had a 10-fold increase in bacteraemia compared to other treatment groups after 24h of infection. This may suggest the significance of pyroptosis in pneumococcal immunity. Finally, I utilised an ex vivo human organ perfusion model to compare the serotype dependent capture of pneumococci in tissue resident macrophages between human and mice. The results showed that serotype dependent capture is more apparent in mice whilst no such activity was recorded in the human liver. Overall, the results of my research emphasises the complexity of host-pathogen responses and the importance of a suitable model to delineate the pathogenesis of infectious diseases.