Center for Translational Neuromedicine, Faculties of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Experimental Medicine Science, Lund University, Lund, Sweden.
Ann Neurol. 2021 Oct;90(4):653-669. doi: 10.1002/ana.26186. Epub 2021 Aug 23.
Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis.
We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis.
Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics.
This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis. ANN NEUROL 2021;90:653-669.
肺炎链球菌是细菌性脑膜炎最常见的病因，尽管采用抗生素治疗，这种疾病在全球范围内仍与高死亡率和高发病率相关。弥漫性脑水肿是肺炎链球菌性脑膜炎发病的主要原因。我们假设中性粒细胞胞外诱捕网（NETs）会破坏通过神经胶质淋巴途径的脑脊液（CSF）转运，并导致肺炎链球菌性脑膜炎时发生水肿。
我们使用 DNAse I 处理来破坏 NETs，然后通过在肺炎链球菌性脑膜炎大鼠模型中对脑池进行 CSF 示踪剂注射，评估神经胶质淋巴途径的功能。
我们的分析表明，在肺炎链球菌性脑膜炎大鼠模型中，CSF 流入脑实质以及 CSF 引流到颈淋巴结的情况明显减少。通过 DNAse 处理降解 NETs 可恢复神经胶质淋巴途径转运，并消除大鼠脑重量的增加。相比之下，一线抗生素治疗对恢复流体动力学没有这种作用。
这项研究表明，CSF 积聚是脑水肿形成的原因，并确定神经胶质淋巴途径和 NETs 可能是肺炎链球菌性脑膜炎的新治疗靶点。
