The Interaction Between Pathogenic Bacteria and Tissue Specific Host Response in Invasive Disease and Pathogenesis

Invasive bacterial disease is a major burden on healthcare worldwide. In serious cases, it can lead to lifelong morbidity or death. This thesis focuses on invasive diseases caused by Streptococcus pneumoniae and Escherichia coli, mainly covering pneumonia, sepsis and meningitis. For S. pneumoniae, I report its presence in the alveolar macrophages of healthy volunteers, and the presence of nasopharyngeal carriage not correlating with intracellular findings. Furthermore, I show that in the early stages of infection in an ex vivo human spleen perfusion, pneumococcal foci of intracellular bacteria increase as time progresses and that anti-pneumococcal IgG can be detected in collected perfusion samples. For E. coli, I explore the possibility of macrophage clearance as a correlate of protection in preclinical immunisation settings. The initial trial was insufficient to procure a protection phenotype, therefore leaving this hypothesis untested. In addition, I tested the viability of a neonatal meningitis pathogenesis in an adult mice model. The results suggest that using adult animals to study neonatal E. coli meningitis infections is a viable option. The resultant infection was further analysed through a quantitative analysis which revealed a clear preference by E. coli to invade endothelial cells in the perivascular spaces. Therefore, furthering the insights into host pathogen interactions of E. coli and S. pneumoniae.