<scp>DNase</scp> Treatment Prevents <scp>Cerebrospinal Fluid</scp> Block in Early Experimental Pneumococcal Meningitis
Chiara Pavan, Anna L. R. Xavier, Marta Ramos, Jane Fisher, Marios Kritsilis, Adam Linder, Peter Bentzer, Maiken Nedergaard, Iben Lundgaard
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.