DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

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.

Dysfunctional glymphatic system with disrupted aquaporin-4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during pneumococcal meningitis

“…On the other hand, Pavan and collaborators have recently observed that upon neuroinflammation caused by a pneumococcal infection in the CNS, AQP4 expression levels are not significantly altered compared to a non-infected situation. Our results go in line with Pavan et al [29], as we did not observe increased AQP4 expression levels in the brains from the meningitis-affected rats compared to the brains from the sham control mice. Significantly, what affects the solute transport of the glymphatic system during pneumococcal meningitis is not the altered AQP4 expression, but rather the disruption of the AQP4-water channels due to a detachment of the astrocytic end feet from the BBB vascular endothelium.…”

“…AQP4 is a water channel present on the end feet of perivascular astrocytes, which are in contact with the vascular endothelium of the BBB, and AQP4-water channels regulate the solute transport of the glymphatic system [26][27][28]. It was recently reported that AQP4 levels are not altered in the brain cerebral cortex during pneumococcal meningitis [29]. In line with these recent findings, our western blot analysis using brain homogenates clearly showed that upon experimental pneumococcal meningitis, AQP4 protein levels are not altered comparing brain tissue of the rats from sham and meningitis groups over time (Figures 8A and 8B).…”

Dysfunctional Glymphatic System with Disrupted Aquaporin 4 Expression Pattern on Astrocytes Causes Bacterial Product Accumulation in the CSF during Pneumococcal Meningitis

“…Intracisternal administration of pneumococci in the CSF progressively caused decreased drainage of CSF into the brain parenchyma and diminished fluid return into the peripheral circulation. This finding is in line with a study by Pavan and collaborators in which it was reported that pneumococcal meningitis induced with intracisternal administration of S. pneumoniae caused accumulation of a fluorescent tracer in the CSF compartment as a consequence of impaired functionality of the glymphatic system ( 11 ). In this study, we newly observed a significant accumulation of pneumolysin and pneumococcal capsule localized in the CSF compartments rather than in the brain parenchyma over time.…”

Neutrophils and aquatic pathogens

“…By using a rat model, it was demonstrated that NET‐formation disrupt cerebrospinal fluid transport. This may elicit oedema in the CNS infected with Streptococcus pneumonia , the most common cause of bacterial meningitis, and thereby exacerbate the disease 20 . This unexpected consequence of NET formation may be considered as a serious collateral damage induced by the NETS.…”

“…This may elicit oedema in the CNS infected with Streptococcus pneumonia , the most common cause of bacterial meningitis, and thereby exacerbate the disease. 20 This unexpected consequence of NET formation may be considered as a serious collateral damage induced by the NETS. DNase treatment disrupting NETs re‐established the fluid transport and thereby prevented brain oedema and weight increase.…”