title: Interleukin-18 deficiency and its long-term behavioural and cognitive impacts in a murine model of pneumococcal meningitis.
abstract: Pneumococcal meningitis often results in death or neurological sequelae, but the underlying pathogenetic mechanisms remain poorly understood. In C57BL/6J mice subjected to intracerebroventricular (icv) challenge with Streptococcus pneumoniae, the chemokine CCL2 and cytokines interferon-γ, interleukin (IL)-1β, IL-6 and tumour necrosis factor were prominently expressed in the brain during the acute phase of the disease. The upregulation of these immune mediators was markedly diminished in IL-18-deficient mice. Uninfected IL-18(-/-) mice exhibited decreases in anxiety phenotype and licking behaviour, and an increase in behavioural habituation, in an automated monitoring system (the IntelliCage). Without antibiotic intervention, a majority of IL-18(+/+) mice developed irreversible disease after icv S. pneumoniae but this was significantly improved by deleting IL-18 gene function. IL-18(+/+) mice cured of pneumococcal meningitis with four doses of ceftriaxone, initiated at 20 h post-inoculation, showed enduring sequelae. These included abnormal behavioural phenotypes featuring diurnal hypoactivity and nocturnal hyperactivity, light phobia and disrupted cognitive function. While the hyperactive phenotype was absent in the corresponding IL-18(-/-) survivors, cognitive impairments and behavioural deficits were still present. Overall, the results suggest that the high levels of cytokines and/or chemokines released after pneumococcal challenge provoked a series of pathological events, ultimately causing acute death. Furthermore, since only a subset of behavioural phenotypes were ameliorated in the pneumococcus-infected IL-18(-/-) mice, the pathological pathways causing mortality may be, at least in part, distinct from those leading to long-term neurological sequelae.
authors: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
authors: L K
authors: LK
authors: Too
authors: The Centenary Institute, Newtown, NSW 2042, Australia.
authors: A J
authors: AJ
authors: Mitchell
authors: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
authors: B
authors: B
authors: Yau
authors: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
authors: H J
authors: HJ
authors: Ball
authors: School of Psychology, University of Sydney, Sydney, NSW 2006, Australia.
authors: I S
authors: IS
authors: McGregor
authors: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: Nicholas.hunt@sydney.edu.au.
authors: N H
authors: NH
authors: Hunt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001007:Anxiety / Q000209:etiology / Q000503:physiopathology*; D002443:Ceftriaxone / Q000627:therapeutic use; D018925:Chemokines / Q000134:cerebrospinal fluid; D002940:Circadian Rhythm / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D016207:Cytokines / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D018450:Disease Progression; D004327:Drinking Behavior / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D006185:Habituation, Psychophysiologic / Q000502:physiology; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008586:Meningitis, Pneumococcal / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D010775:Photic Stimulation
chemical_list: D000900:Anti-Bacterial Agents; D018925:Chemokines; D016207:Cytokines; D020382:Interleukin-18; D002443:Ceftriaxone
keywords: Cytokine; IntelliCage; Interleukin-18; Neurological sequelae; Pneumococcal meningitis