Interleukin-18 deficiency and its long-term behavioural and cognitive impacts in a murine model of pneumococcal meningitis

• IL-18 mediates the inflammatory response during acute pneumococcal meningitis.
• IL-18 deficiency improves survival of mice during brain infection with pneumococci.
• IL-18 deficiency diminishes behavioural sequelae due to pneumococcal meningitis.
• IL-18 is not responsible for cognition impairment caused by pneumococcal meningitis.
• IL-18-mediated cytokine dysfunction may contribute to mortality and/or morbidity.

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.