title: The pro-inflammatory cytokine interferon-gamma is an important driver of neuropathology and behavioural sequelae in experimental pneumococcal meningitis.
abstract: Interferon-gamma is known to play a complex modulatory role in immune defence during microbial infections. Its actions in pneumococcal meningitis, however, remain ill-defined. Here, a pathological role for IFN-γ was demonstrated using a murine model of pneumococcal meningitis, in that C57BL/6J mice deficient in this pro-inflammatory cytokine (IFN-γ(-/-)) showed less severe acute and long-term neuropathology following intracerebral challenge with Streptococcus pneumoniae. The absence of IFN-γ significantly lengthened the survival of mice that otherwise would have developed fatal clinical signs within two days of CNS infection. Compared to their wild-type counterparts, IFN-γ(-/-) mice showed a diminished inflammatory response (attenuated levels of pro-inflammatory cytokines in the cerebrospinal fluid) and milder brain pathologies (less BBB permeability to protein and brain haemorrhage) during the acute phase of disease. Following a full regime of antibiotic treatment, we found substantial brain injuries in the wild-type mice 10days after infection. IFN-γ(-/-) mice, however, showed decreased neuronal damage in both hippocampus and cortex. In the longer term (≈10weeks p.i.), the wild-type mice that had survived meningitis due to antibiotic treatment had neurobehavioural abnormalities including diurnal hypoactivity, nocturnal hyperactivity and impaired performance in a discrimination reversal task. IFN-γ(-/-) mice, concomitantly tested in the automated IntelliCage platform, had reduced behavioural and cognitive disorders compared to wild-type mice. Both IFN-γ(-/-) and wild-type survivors of pneumococcal meningitis showed impaired working memory in the IntelliCage-based complex patrolling task. These observations indicate an association between IFN-γ-driven acute brain pathology and the long-term neurological sequelae resulting from pneumococcal meningitis.
authors.affiliation: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: L K
authors.initials: LK
authors.lastname: Too
authors.affiliation: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.affiliation: School of Psychology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Iain S
authors.initials: IS
authors.lastname: McGregor
authors.affiliation: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address: Nicholas.hunt@sydney.edu.au.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000150:complications; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008297:Male; D008586:Meningitis, Pneumococcal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D007371:Interferon-gamma
keywords: Central nervous system; Cytokine; IntelliCage; Interferon-gamma; Neurological disease; Neurological sequelae; Neuropathology; Pneumococcal meningitis