Abstract
BackgroundS. pneumoniae is the most common causative agent of meningitis, and is associated with high morbidity and mortality. We aimed to develop an integrated and representative pneumococcal meningitis mouse model resembling the human situation.MethodsAdult mice (C57BL/6) were inoculated in the cisterna magna with increasing doses of S. pneumoniae serotype 3 colony forming units (CFU; n = 24, 104, 105, 106 and 107 CFU) and survival studies were performed. Cerebrospinal fluid (CSF), brain, blood, spleen, and lungs were collected. Subsequently, mice were inoculated with 104 CFU S. pneumoniae serotype 3 and sacrificed at 6 (n = 6) and 30 hours (n = 6). Outcome parameters were bacterial outgrowth, clinical score, and cytokine and chemokine levels (using Luminex®) in CSF, blood and brain. Meningeal inflammation, neutrophil infiltration, parenchymal and subarachnoidal hemorrhages, microglial activation and hippocampal apoptosis were assessed in histopathological studies.ResultsLower doses of bacteria delayed onset of illness and time of death (median survival CFU 104, 56 hrs; 105, 38 hrs, 106, 28 hrs. 107, 24 hrs). Bacterial titers in brain and CSF were similar in all mice at the end-stage of disease independent of inoculation dose, though bacterial outgrowth in the systemic compartment was less at lower inoculation doses. At 30 hours after inoculation with 104 CFU of S. pneumoniae, blood levels of KC, IL6, MIP-2 and IFN- γ were elevated, as were brain homogenate levels of KC, MIP-2, IL-6, IL-1β and RANTES. Brain histology uniformly showed meningeal inflammation at 6 hours, and, neutrophil infiltration, microglial activation, and hippocampal apoptosis at 30 hours. Parenchymal and subarachnoidal and cortical hemorrhages were seen in 5 of 6 and 3 of 6 mice at 6 and 30 hours, respectively.ConclusionWe have developed and validated a murine model of pneumococcal meningitis.
Highlights
S. pneumoniae is the most common causative agent of meningitis, and is associated with high morbidity and mortality
Autopsy studies of patients who died following pneumococcal meningitis revealed cerebral edema, cerebral infarctions and hemorrhages, apoptosis and necrosis of the hippocampal dentate gyrus [9,10,11]. Many of these pathological features have been reproduced in animal models, which provide the setting for novel drug development and pathophysiological studies [12,13]
We developed a murine model of pneumococcal meningitis in which the histopathological and inflammatory features as well as observed complications resemble clinical and pathological findings in humans following bacterial meningitis [1,20]
Summary
S. pneumoniae is the most common causative agent of meningitis, and is associated with high morbidity and mortality. The most common pathogen beyond the neonatal period is Streptococcus pneumoniae [1,3], causing 70% of cases. Autopsy studies of patients who died following pneumococcal meningitis revealed cerebral edema, cerebral infarctions and hemorrhages, apoptosis and necrosis of the hippocampal dentate gyrus [9,10,11]. Many of these pathological features have been reproduced in animal models, which provide the setting for novel drug development and pathophysiological studies [12,13]
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