Pathophysiology of pneumococcal meningitis

Bacterial meningitis is a serious infectious disease, involving the membranes surrounding the brain and spinal cord, and the subarachnoid space. In the Netherlands most common causative agents are Streptococcus pneumoniae (72%) and Neisseria meningitidis (11%). The incidence of pneumococcal meningitis in the Netherlands is 0.7 per 100.000, and has rapidly declined over the last decade as a result of herd immunity established by the introduction of a pneumococcal conjugate vaccine in the national childhood immunization programme. However, mortality and morbidity of pneumococcal meningitis remain high. In chapter 2 the pathophysiology of pneumococcal meningitis is reviewed. We discuss the different routes of infection, the host innate and adaptive immune response, brain damage described in humans and different animal models and potential targets for adjunctive therapy. In chapter 3 we describe the development and validation of an experimental mouse model for pneumococcal meningitis. We describe the different features of the immune response and pathophysiology. This animal model is used to study the role of the inflammasome pathway in the pathogenesis of pneumococcal meningitis in chapter 4. In chapter 5 we describe the association of a single-nucleotide polymorphism in two genes that are involved in the inflammasome-signaling pathway with unfavorable outcome in patients with pneumococcal meningitis. In chapter 6 we show that pneumococcal virulence also plays a role in the outcome of pneumococcal meningitis in patients. The absence of a pneumococcal arginine synthetase system is associated with favorable outcome in patients. In chapter 7 we report an explorative study in which we measured a large set of inflammatory mediators in the CSF of patients with pneumococcal meningitis. In chapter 8 we discuss our results with regard to other studies, we address any methodological shortcomings and give directions for future research