Abstract
BackgroundListeria monocytogenes is a common cause of bacterial meningitis. We developed an animal model of listerial meningitis.MethodsIn survival studies, C57BL/6 mice received intracisternal injections with different L. monocytogenes sequence type 1 (ST1) colony forming units per milliliter (CFU; n = 48, 105, 106, 107, 108, and 109 CFU/ml). Second, mice were inoculated with 108 CFU/ml ST1 and sacrificed at 6 h and 24 h (n = 12/group). Outcome parameters were clinical score, CFUs, cyto- and chemokine levels, and brain histopathology. Third, 84 mice were inoculated (109 CFU/ml ST1) to determine optimal antibiotic treatment with different doses of amoxicillin and gentamicin. Fourth, mice were inoculated with 109 CFU/ml ST1, treated with amoxicillin, and sacrificed at 16 h and 24 h (n = 12/group) for outcome assessment. Finally, time point experiments were repeated with ST6 (n = 24/group).ResultsMedian survival time for inoculation with 108 and 109 CFU/ml ST1 was 46 h and 40 h; lower doses of bacteria led to minimal clinical signs of disease. Brain levels of IL-6, IL-17A, and IFN-γ were elevated at 24 h, and IL-1β, IL-6, IL-10, IFN-γ, and TNF-α were elevated in blood at 6 h and 24 h. Histopathology showed increased meningeal infiltration, vascular inflammation of meningeal vessels, hemorrhages, and ventriculitis. In the treatment model, brain levels of IL-6 and IL-17A and blood levels of IL-6 and IFN-γ were elevated. Compared to ST6, infection with ST1 led initially to higher levels of IL-1β and TNF-α in blood and more profound neuropathological damage. At 16 h post inoculation, IL-1β, IL-10, and TNF-α in blood and IL-6, IL17A, TNF-α, and IFN-γ levels in brain were higher in ST1 compared to ST6 without differences in CFUs between STs. At 24 h, neuropathology score was higher in ST1 compared to ST6 (p = 0.002) infected mice.ConclusionsWe developed and validated a murine model of listerial meningitis. ST1-infected mice had a more severe inflammatory response and brain damage as compared to ST6-infected mice.
Highlights
Listeria monocytogenes is a common cause of bacterial meningitis
Non-treatment model In the survival study, mice inoculated with 105, 106 and 107 colony forming units per milliliter (CFU)/ml L. monocytogenes sequence type 1 (ST1) showed minimal clinical signs of disease limited to diminished grooming and/ or a slightly hunched back. They had to be sacrificed based on weight loss, ≥ 25% according to the predefined endpoint in the clinical scoring (Fig. 1a), and considered not representable for a listerial meningitis model
Mice inoculated with 108 CFU/ml L. monocytogenes ST1 showed signs of illness 12 h after inoculation, consisting of discharge in eyes, a slightly hunched back, mildly diminished activity and/or piloerection, and had a median survival time of 46 h (IQR 34–52 h; Fig. 1b)
Summary
Listeria monocytogenes is a common cause of bacterial meningitis. Several mouse and rat listeria models have been developed to study invasive L. monocytogenes diseases including cerebral and meningeal infection, using oral [15,16,17], intravenous [18], intracerebral [19,20,21,22,23], or intracisternal inoculation methods [24,25,26]. Problems with reproducibility, limited disease progression, or iatrogenic structural damage, combined with a need for a single model in which most pathological features seen in human listerial meningitis can be measured, have created the need for development of a new animal model. We developed a listerial meningitis mouse model to counter these problems and compared infection with listerial ST1 with ST6
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