Department of Neuropathology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany.
Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, Göttingen, Germany.
J Neuropathol Exp Neurol. 2021 Sep 27;80(9):861-867. doi: 10.1093/jnen/nlab079.
To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p < 0.0001) was found. A decreased density of dividing cells stained with an anti-PCNA-antibody (p < 0.0001) and less neurogenesis visualized by anti-calretinin (p < 0.0001) and anti-calbindin (p = 0.01) antibodies were detected compared to uninfected controls. The density of microglia was higher in LM meningitis (p < 0.0001), while the density of astrocytes remained unchanged. Infiltrating monocytes and neutrophilic granulocytes likely contributed to tissue damage. In conclusion, in the brains of LM-infected mice a strong immune response was observed which led to neuronal apoptosis and an impaired neural regeneration. This model appears very suitable to study therapies against long-term sequelae of neonatal LM meningitis.
为了改善新生儿中枢神经系统感染的治疗方法，迫切需要建立特征明确的动物模型。本研究分析了神经病理学改变，尤其关注李斯特菌（LM）脑膜炎/脑膜脑炎新生小鼠模型中神经损伤和修复。通过组织学、免疫组织化学和原位末端标记分析了 14 例 LM 脑膜炎/脑膜脑炎新生小鼠和 14 例未感染对照小鼠的海马结构和额皮质。LM 脑膜炎/脑膜脑炎小鼠的海马齿状回中，原位末端标记（p = 0.04）和原位末端标记加活化 Caspase-3 免疫组化（p < 0.0001）显示凋亡神经元密度增加。与未感染对照相比，增殖细胞密度（用抗 PCNA 抗体染色）降低（p < 0.0001），神经发生减少（用抗钙调蛋白和抗钙结合蛋白抗体可视化）（p < 0.0001）。LM 脑膜炎时小胶质细胞密度更高（p < 0.0001），而星形胶质细胞密度不变。浸润的单核细胞和嗜中性粒细胞可能导致组织损伤。总之，在 LM 感染的小鼠脑中观察到强烈的免疫反应，导致神经元凋亡和神经再生受损。该模型似乎非常适合研究针对新生儿 LM 脑膜炎后遗症的治疗方法。
