From the Amsterdam UMC, Department of Neurology, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
J Neuroinflammation. 2018 Sep 7;15(1):257. doi: 10.1186/s12974-018-1293-3.
Listeria monocytogenes is a common cause of bacterial meningitis. We developed an animal model of listerial meningitis.
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, 10, 10, 10, 10, and 10 CFU/ml). Second, mice were inoculated with 10 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 (10 CFU/ml ST1) to determine optimal antibiotic treatment with different doses of amoxicillin and gentamicin. Fourth, mice were inoculated with 10 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).
Median survival time for inoculation with 10 and 10 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.
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.
李斯特菌是细菌性脑膜炎的常见病因。我们建立了李斯特菌脑膜炎的动物模型。
在生存研究中，C57BL/6 小鼠接受不同李斯特菌 1 型序列型（ST1）集落形成单位/毫升（CFU；n=48、10、10、10、10 和 10 CFU/ml）的脑室内注射。其次，小鼠接种 10 CFU/ml ST1，在 6 小时和 24 小时处死（n=12/组）。观察指标为临床评分、CFU、细胞因子和趋化因子水平及脑组织病理学。第三，将 84 只小鼠接种（10 CFU/ml ST1），以确定不同剂量阿莫西林和庆大霉素的最佳抗生素治疗方案。第四，小鼠接种 10 CFU/ml ST1，给予阿莫西林治疗，在 16 小时和 24 小时处死（n=12/组）进行结果评估。最后，用 ST6（n=24/组）重复时间点实验。
接种 10 和 10 CFU/ml ST1 的中位生存时间分别为 46 小时和 40 小时；较低剂量的细菌导致疾病的临床症状最小。24 小时时脑内 IL-6、IL-17A 和 IFN-γ 水平升高，6 小时和 24 小时时血中 IL-1β、IL-6、IL-10、IFN-γ 和 TNF-α水平升高。组织病理学显示脑膜浸润增加、脑膜血管血管炎症、出血和脑室炎。在治疗模型中，脑内 IL-6 和 IL-17A 以及血中 IL-6 和 IFN-γ 水平升高。与 ST6 相比，感染 ST1 导致血中初始 IL-1β和 TNF-α水平升高，神经病理学损伤更严重。接种后 16 小时，与 ST6 相比，ST1 组血中 IL-1β、IL-10 和 TNF-α以及脑内 IL-6、IL17A、TNF-α和 IFN-γ 水平升高，但 ST 间 CFU 无差异。24 小时时，ST1 感染小鼠的神经病理学评分高于 ST6 感染小鼠（p=0.002）。
我们建立并验证了李斯特菌脑膜炎的小鼠模型。与 ST6 感染小鼠相比，ST1 感染小鼠表现出更严重的炎症反应和脑损伤。
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