title: Interferon-γ-Induced Nitric Oxide Synthase-2 Contributes to Blood/Brain Barrier Dysfunction and Acute Mortality in Experimental Streptococcus pneumoniae Meningitis.
abstract: The proinflammatory cytokine interferon-gamma (IFNγ) recently was shown to play a crucial role in experimental pneumococcal meningitis (PM) pathogenesis, and we aimed in this study to investigate IFNγ-driven nitric oxide synthase-2 (NOS2)-mediated pathogenesis of murine PM. We demonstrate that costimulation of toll-like receptors and IFNγ receptors was synergistic for NOS2 expression in cultured murine microglia. Using an experimental PM model, wild-type mice treated with anti-IFNγ antibody, as well as IFNγ and NOS2 gene knockout (GKO) mice, were inoculated intracerebroventricularly with 10(3) colony-forming units of Streptococcus pneumoniae (WU2 strain). Mice were monitored daily during a 200-h disease course to assess survival rate and blood-brain barrier (BBB) permeability measured at 48 h. IFNγ deficiency was protective in PM, with an approximate 3-fold increase in survival rates in both antibody-treated and IFNγ GKO mice compared to controls (P < 0.01). At 48 h postinoculation, brain NOS2 mRNA expression was significantly increased in an IFNγ-dependent manner. Mortality was significantly delayed in NOS2 GKO mice compared to controls (P < 0.01), and BBB dysfunction was reduced by 54% in IFNγ GKO mice and abolished in NOS2 GKO. These data suggest that IFNγ-dependent expression of NOS2 in the brain contributes to BBB breakdown and early mortality in murine PM.
authors.affiliation: 1 Molecular Immunopathology Unit, School of Medical Sciences, Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia .
authors.forename: Belinda
authors.initials: B
authors.lastname: Yau
authors.affiliation: 1 Molecular Immunopathology Unit, School of Medical Sciences, Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia .|2 Centenary Institute for Cancer Medicine and Cell Biology , Newtown, New South Wales, Australia .
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mitchell
authors.affiliation: 1 Molecular Immunopathology Unit, School of Medical Sciences, Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia .
authors.forename: Lay Khoon
authors.initials: LK
authors.lastname: Too
authors.affiliation: 1 Molecular Immunopathology Unit, School of Medical Sciences, Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia .
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.affiliation: 1 Molecular Immunopathology Unit, School of Medical Sciences, Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia .
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism*; D008586:Meningitis, Pneumococcal / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species; D013296:Streptococcus pneumoniae; D051193:Toll-Like Receptors / Q000819:agonists
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II