Characterization of a Listeria monocytogenes meningitis mouse model

Background: Listeria monocytogenes is a common cause of bacterial meningitis. We developed an animal model of listerial meningitis. Methods: In 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 109CFU/ml). Second, mice were inoculated with 108CFU/ml ST1 and sacrificed at 6h and 24h (n=12/group). Outcome parameters were clinical score, CFUs, cyto- and chemokine levels, and brain histopathology. Third, 84 mice were inoculated (109CFU/ml ST1) to determine optimal antibiotic treatment with different doses of amoxicillin and gentamicin. Fourth, mice were inoculated with 109CFU/ml ST1, treated with amoxicillin, and sacrificed at 16h and 24h (n=12/group) for outcome assessment. Finally, time point experiments were repeated with ST6 (n=24/group). Results: Median survival time for inoculation with 108 and 109CFU/ml ST1 was 46h and 40h; lower doses of bacteria led to minimal clinical signs of disease. Brain levels of IL-6, IL-17A, and IFN-γ were elevated at 24h, and IL-1β, IL-6, IL-10, IFN-γ, and TNF-α were elevated in blood at 6h and 24h. 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 16h 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 24h, neuropathology score was higher in ST1 compared to ST6 (p=0.002) infected mice. Conclusions: We 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.