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Brain Behav Immun. 2014 Aug;40:252-68. doi: 10.1016/j.bbi.2014.02.020. Epub 2014 Mar 7.

The pro-inflammatory cytokine interferon-gamma is an important driver of neuropathology and behavioural sequelae in experimental pneumococcal meningitis.

Author information

1
Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
2
School of Psychology, University of Sydney, Sydney, New South Wales 2006, Australia.
3
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.

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.

KEYWORDS:

Central nervous system; Cytokine; IntelliCage; Interferon-gamma; Neurological disease; Neurological sequelae; Neuropathology; Pneumococcal meningitis

PMID:
24607660
DOI:
10.1016/j.bbi.2014.02.020
[Indexed for MEDLINE]
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