Pathogenesis of pneumococcal meningitis

Abstract

Streptococcus pneumoniae (SP) meningitis remains a significant cause of global childhood mortality, and a potential epidemic pathogen despite improving vaccinations schemes. Neuropathology in pneumococcal meningitis (PM) is attributed to both bacterial products and the host-mediated proinflammatory response. Proinflammatory cytokine interferon-gamma (IFNγ) is associated with macrophage activation and regulating MHC Class I expression in innate immunity. IFNγ gene knockout (GKO) mice inoculated with ~5 x 103 CFU of SP/mouse were significantly protected against fatal PM, compared to C57Bl/6 WT mice, in both serotype 3 WU2 and serotype 4 TIGR4 strains. TIGR4 PM was comparatively more virulent than WU2 PM. In murine PM, IFNγ regulated induction of chemokines MCP1, CXCL9, CXCL10, the IRGM1, IRGM3 proteins and nitric oxide synthase 2 (NOS2). In WU2 PM, production of IFNγ was attributed to infiltrating Natural Killer (NK) cells, and dependent upon activation of the inflammasome complex and interleukin-18. NOS2 GKO exhibited a significantly improved survival phenotype, and reduced blood brain barrier dysfunction, compared to WT mice. Intracellular staining revealed Ly6Chi monocytes and NK cells as the source of IFNγ-dependent NOS2 in PM. Overall, this thesis addresses IFNγ production and its contribution to experimental PM pathology