Interleukin-18 deficiency and its long-term behavioural and cognitive impacts in a murine model of pneumococcal
L K Too1, A J Mitchell2, B Yau1
1Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
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.
Insights
Interleukin-18 (IL-18) deficiency protects mice from death and some neurological deficits caused by pneumococcal meningitis. However, deleting IL-18 does not fully prevent long-term behavioral and cognitive impairments following infection.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Pneumococcal meningitis can cause death or lasting neurological problems, but the exact causes are unclear.
- Key immune molecules like chemokines and cytokines are involved in the brain during acute meningitis.
Purpose of the Study:
- To investigate the role of interleukin-18 (IL-18) in the pathogenesis of pneumococcal meningitis and its long-term neurological consequences.
- To determine if IL-18 deficiency impacts disease severity, mortality, and behavioral sequelae after Streptococcus pneumoniae infection in mice.
Main Methods:
- Intracerebroventricular (icv) challenge with Streptococcus pneumoniae in C57BL/6J mice, including IL-18-deficient (IL-18(-/-)) and wild-type (IL-18(+/+)) littermates.
- Monitoring of immune mediator expression (chemokines, cytokines) in the brain.
- Behavioral assessment using the IntelliCage system to evaluate anxiety, habituation, and activity patterns.
- Evaluation of neurological sequelae in surviving mice after antibiotic treatment.
Main Results:
- IL-18(-/-) mice showed significantly reduced expression of brain immune mediators during acute infection compared to IL-18(+/+) mice.
- IL-18 deficiency markedly improved survival rates in mice challenged with S. pneumoniae without antibiotic treatment.
- While IL-18(-/-) survivors showed fewer behavioral abnormalities than IL-18(+/+) survivors, cognitive impairments and some behavioral deficits persisted.
Conclusions:
- High levels of cytokines and chemokines, potentially modulated by IL-18, contribute to acute mortality in pneumococcal meningitis.
- The pathological pathways leading to death and long-term neurological sequelae may be partially distinct.
- IL-18 plays a significant role in the acute inflammatory response and mortality but not entirely in the development of chronic neurological deficits after pneumococcal meningitis.
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